TW202400787A - Galnac compositions for improving sirna bioavailability - Google Patents
Galnac compositions for improving sirna bioavailability Download PDFInfo
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- TW202400787A TW202400787A TW112109623A TW112109623A TW202400787A TW 202400787 A TW202400787 A TW 202400787A TW 112109623 A TW112109623 A TW 112109623A TW 112109623 A TW112109623 A TW 112109623A TW 202400787 A TW202400787 A TW 202400787A
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- alkyl
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- oligonucleotide
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Abstract
Description
心血管病症、代謝疾病及肝相關病症很豐富,且可影響許多人。需要經改良治療劑用於治療此等病症。Cardiovascular, metabolic, and liver-related conditions are abundant and can affect many people. There is a need for improved therapeutic agents for the treatment of these conditions.
本文揭示一種由式(I)或(II)表示之化合物: ; 或其鹽,其中 J為寡核苷酸; 各w獨立地選自1至20之任何值; 各v獨立地選自1至20之任何值; n選自1至20之任何值; m選自1至20之任何值; z選自1至3之任何值,其中 若z為3,則Y為C, 若z為2,則Y為CR 6,或 若z為1,則Y為C(R 6) 2; Q選自: 視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7 、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中該C 1-6烷基視情況經一或多個獨立地選自鹵素、-CN、-OH、-SH、-NO 2及-NH 2之取代基取代; R 1為選自以下之連接子: -O-、-S-、-N(R 7)-、-C(O)-、-C(O)N(R 7)-、-N(R 7)C(O)-、-N(R 7)C(O)N(R 7)-、-OC(O)N(R 7)-、-N(R 7)C(O)O-、-C(O)O-、-OC(O)-、-S(O)-、-S(O) 2-、-OS(O) 2-、-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7-; 各R 2獨立地選自: 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; R 3及R 4各自獨立地選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 5獨立地選自: -OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2; 各R 6獨立地選自: 氫; 鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 7獨立地選自: 氫; C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及 C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。 在一些實施例中,各w獨立地選自1至10之任何值。在一些實施例中,各w獨立地選自1至5之任何值。在一些實施例中,各w為1。在一些實施例中,各v獨立地選自1至10之任何值。在一些實施例中,各v獨立地選自1至5之任何值。在一些實施例中,各v為1。在一些實施例中,n選自1至10之任何值。在一些實施例中,n選自1至5之任何值。在一些實施例中,n為2。在一些實施例中,m選自1至10之任何值。在一些實施例中,m選自1至5之任何值。在一些實施例中,m選自1及2。在一些實施例中,z為3且Y為C。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基。在一些實施例中,Q選自環己基。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-及-OP(OR 7)O-。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(OR 7)O-。在一些實施例中,R 1選自-OP(O)(OR 7)O-及-OP(OR 7)O-。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:鹵素、-OR 7、-OC(O)R 7、-SR 7、-N(R 7) 2、-C(O)R 7及-S(O)R 7。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7及-OC(O)R 7。在一些實施例中,R 3選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,R 3選自-OR 7、-SR 7、-OC(O)R 7及-N(R 7) 2。在一些實施例中,R 3選自-OR 7-及-OC(O)R 7。在一些實施例中,R 4選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,R 4選自-OR 7、-SR 7、-OC(O)R 7及-N(R 7) 2。在一些實施例中,R 4選自-OR 7-及-OC(O)R 7。在一些實施例中,R 5選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2及-N(R 7)C(O)OR 7。在一些實施例中,R 5選自-OC(O)R 7及-N(R 7)C(O)R 7。在一些實施例中,各R 7獨立地選自:氫;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,或3至10員雜環。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH及-SH。在一些實施例中,w為1;v為1;n為2;m為1或2;z為3且Y為C;Q為苯基或環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2及C 1-3烷基;R 1選自-OP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(OR 7)O-;R 2為經-OH或-OC(O)CH 3取代之C 1烷基;R 3為-OH或-OC(O)CH 3;R 4為-OH或-OC(O)CH 3;及R 5為-NH(O)CH 3。在一些實施例中,化合物包含: 。 在一些實施例中,寡核苷酸(J)連接在寡核苷酸之5'端或3'端。在一些實施例中,寡核苷酸包含DNA。在一些實施例中,寡核苷酸包含RNA。在一些實施例中,寡核苷酸包含一或多個經修飾之核苷間鍵聯。在一些實施例中,該一或多個經修飾之核苷間鍵聯包含烷基膦酸酯、硫代磷酸酯、甲基磷酸酯、二硫代磷酸酯、烷基硫代磷酸酯(alkylphosphonothioate)、胺基磷酸酯、胺基甲酸酯、碳酸酯、磷酸三酯、乙醯胺酸酯或羧甲基酯,或其組合。在一些實施例中,寡核苷酸包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個經修飾之核苷間鍵聯。在一些實施例中,寡核苷酸包含一或多個經修飾之核苷。在一些實施例中,該一或多個經修飾之核苷包含鎖核酸(locked nucleic acid;LNA)、己糖醇核酸(HLA)、環己烯核酸(CeNA)、2'-甲氧基乙基、2'-O-烷基、2'-O-烯丙基、2'-O-烯丙基、2'-氟或2'-去氧基,或其組合。在一些實施例中,該一或多個經修飾之核苷包含2',4'經約束之乙基核苷、2'-O-甲基核苷、2'-去氧基氟核苷、2'-O-N-甲基乙醯胺基(2'-O-NMA)核苷、2'-O-二甲基胺基乙氧基乙基(2'-O-DMAEOE)核苷、2'-O-胺基丙基(2'-O-AP)核苷、2'-ara-F、2'氟基或2'-O-烷基,或其組合。在一些實施例中,寡核苷酸包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21或更多個經修飾之核苷。在一些實施例中,寡核苷酸包含連接在寡核苷酸之3'或5'端之脂質。在一些實施例中,脂質包含膽固醇、肉豆蔻醯基、軟脂醯基、硬脂醯基、石膽醯基(lithocholoyl)、二十二烷醯基、二十二碳六烯醯基(docosahexaenoyl)、肉豆蔻基、軟脂基、硬脂基或α-生育酚,或其組合。在一些實施例中,寡核苷酸包含連接在寡核苷酸之3'或5'端之精胺酸-甘胺酸-天冬胺酸(RGD)肽。在一些實施例中,RGD肽包含環(-Arg-Gly-Asp-D-Phe-Cys)、環(-Arg-Gly-Asp-D-Phe-Lys)、環(-Arg-Gly-Asp-D-Phe-疊氮基)、胺基苯甲酸衍生之RGD或其組合。在一些實施例中,寡核苷酸包含含有有義股及反義股之小干擾RNA (siRNA)。在一些實施例中,有義股之長度為12-30個核苷。在一些實施例中,反義股之長度為12-30個核苷。在一些實施例中,有義股及反義股形成雙股RNA雙螺旋體。在一些實施例中,雙股RNA雙螺旋體之第一鹼基對為AU鹼基對。在一些實施例中,有義股或反義股包含3'懸垂物。在一些實施例中,3'懸垂物包含1、2或更多個核苷。在一些實施例中,有義股包含修飾模式1S至6S或1S#2至6S#2中之任一者。在一些實施例中,反義股包含修飾模式1AS至9AS中之任一者。在一些實施例中,寡核苷酸包含反義寡核苷酸(ASO)。在一些實施例中,ASO之長度為12-30個核苷。在一些實施例中,ASO包含修飾模式ASO1。在一些實施例中,化合物與去唾液酸糖蛋白受體結合。在一些實施例中,該化合物靶向肝細胞。 Disclosed herein is a compound represented by formula (I) or (II): ; Or a salt thereof, wherein J is an oligonucleotide; Each w is independently selected from any value from 1 to 20; Each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where if z is 3, then Y is C, if z is 2, then Y is CR 6 , or if z is 1, then Y is C(R 6 ) 2 ; Q is selected from: C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C (O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from halogen, -CN, -OH, -SH, -NO 2 and -NH 2 is substituted with a substituent; R 1 is a linker selected from the following: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 ) C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -OP(O) (OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - ) O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )- and -OPN(R 7 ) 2 NR 7 -; each R 2 is independently selected from: In the case of C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , - C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 are each independently selected from : -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 ) C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O) OR 7 and -C(O)N(R 7 ) 2 ; each R 6 is independently selected from: hydrogen; halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , - C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , - OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 7 is independently selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each optionally substituted with one or more substituents independently selected from the following: halogen, - CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH (C 1-6 alkyl), C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring, each with one or more as appropriate Substituted with substituents independently selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl , -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 carbon Ring, 3 to 10 membered heterocycle, and C 1-6 haloalkyl. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and - S(O)R 7 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O )(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)( O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N (R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-and -OPN(R 7 ) 2 NR 7 . In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O )(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)( O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, and -OP(OR 7 )O-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S )(O - )O-, -OP(O)(S - )O- and -OP(OR 7 )O-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O- and -OP(OR 7 )O-. In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 and -S(O)R 7 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 , -OC(O)R 7 , -SR 7 and -N (R 7 ) 2 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 and -OC(O)R 7 . In some embodiments, R 3 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, R 3 is selected from -OR 7 , -SR 7 , -OC(O)R 7 and -N(R 7 ) 2 . In some embodiments, R 3 is selected from -OR 7 - and -OC(O)R 7 . In some embodiments, R 4 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, R 4 is selected from -OR 7 , -SR 7 , -OC(O)R 7 and -N(R 7 ) 2 . In some embodiments, R 4 is selected from -OR 7 - and -OC(O)R 7 . In some embodiments, R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C (O)N(R 7 ) 2 and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 . In some embodiments, each R is independently selected from : hydrogen; and optionally C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, or 3 to 10 membered heterocyclic ring. In some embodiments, each R is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl) . In some embodiments, each R 7 is independently selected from C 1-6 alkyl, optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each independently modified by one or more Substituted with substituents selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 and C 1-3 alkyl; R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O- and -OP (OR 7 )O-; R 2 is C 1 alkyl substituted by -OH or -OC(O)CH 3 ; R 3 is -OH or -OC(O)CH 3 ; R 4 is -OH or -OC (O)CH 3 ; and R 5 is -NH(O)CH 3 . In some embodiments, the compound includes: . In some embodiments, oligonucleotide (J) is linked to the 5' end or the 3' end of the oligonucleotide. In some embodiments, the oligonucleotide comprises DNA. In some embodiments, the oligonucleotide comprises RNA. In some embodiments, oligonucleotides comprise one or more modified internucleoside linkages. In some embodiments, the one or more modified internucleoside linkages comprise alkylphosphonate, phosphorothioate, methylphosphate, phosphorodithioate, alkylphosphonothioate ), aminophosphate, carbamate, carbonate, phosphate triester, acetamate or carboxymethyl ester, or combinations thereof. In some embodiments, the oligonucleotide comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 A modified internucleoside linkage. In some embodiments, oligonucleotides comprise one or more modified nucleosides. In some embodiments, the one or more modified nucleosides include locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl base, 2'-O-alkyl, 2'-O-allyl, 2'-O-allyl, 2'-fluoro or 2'-deoxy, or a combination thereof. In some embodiments, the one or more modified nucleosides comprise 2',4' constrained ethyl nucleosides, 2'-O-methyl nucleosides, 2'-deoxyfluoronucleosides, 2'-ON-methylacetamide (2'-O-NMA) nucleoside, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2' -O-aminopropyl (2'-O-AP) nucleoside, 2'-ara-F, 2'fluoro or 2'-O-alkyl, or combinations thereof. In some embodiments, the oligonucleotides comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21 or more modified nucleosides. In some embodiments, the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid includes cholesterol, myristyl, palmityl, stearyl, lithocholoyl, docosyl, docosahexaenoyl ), myristyl, palmityl, stearyl or alpha-tocopherol, or combinations thereof. In some embodiments, the oligonucleotide comprises an arginine-glycine-aspartate (RGD) peptide linked to the 3' or 5' end of the oligonucleotide. In some embodiments, the RGD peptide comprises cyclo(-Arg-Gly-Asp-D-Phe-Cys), cyclo(-Arg-Gly-Asp-D-Phe-Lys), cyclo(-Arg-Gly-Asp- D-Phe-azido), aminobenzoic acid-derived RGD, or combinations thereof. In some embodiments, the oligonucleotides comprise small interfering RNA (siRNA) containing a sense strand and an antisense strand. In some embodiments, the sense strand is 12-30 nucleotides in length. In some embodiments, the antisense strand is 12-30 nucleotides in length. In some embodiments, the sense strand and antisense strand form a double-stranded RNA duplex. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair. In some embodiments, the sense or antisense strand contains a 3' overhang. In some embodiments, the 3' overhang contains 1, 2, or more nucleosides. In some embodiments, the sense strand includes any of modification patterns 1S to 6S or 1S#2 to 6S#2. In some embodiments, the antisense strand comprises any of modification patterns 1AS to 9AS. In some embodiments, the oligonucleotides comprise antisense oligonucleotides (ASOs). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO includes modification pattern ASO1. In some embodiments, the compound binds to the asialoglycoprotein receptor. In some embodiments, the compounds target hepatocytes.
本文揭示一種醫藥組合物,其包含本文所描述之化合物中之任一者的化合物,及醫藥學上可接受之載劑、賦形劑或稀釋劑。在一些實施例中,醫藥組合物為無菌的。在一些實施例中,醫藥組合物包含醫藥學上可接受之載劑。在一些實施例中,醫藥學上可接受之載劑包含水、緩衝液或鹽水溶液。在一些實施例中,寡核苷酸靶向目標mRNA,且當以有效量向個體投與時,使目標mRNA或目標蛋白降低至少10%。Disclosed herein is a pharmaceutical composition comprising a compound of any one of the compounds described herein, and a pharmaceutically acceptable carrier, excipient or diluent. In some embodiments, pharmaceutical compositions are sterile. In some embodiments, pharmaceutical compositions include a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes water, buffer, or saline solution. In some embodiments, the oligonucleotide targets the target mRNA and, when administered to an individual in an effective amount, reduces the target mRNA or target protein by at least 10%.
本文揭示一種降低有需要之個體中之目標mRNA或目標蛋白之方法,其包含投與有效量之本文所描述之化合物中之任一者之醫藥組合物。在一些實施例中,相對於基線目標mRNA或目標蛋白量測,該有效量降低個體中目標mRNA或目標蛋白之量測。在一些實施例中,該有效量治療個體之病症。在一些實施例中,相對於基線症狀或參數量測,該有效量降低個體中與病症相關之症狀或參數的量測。在一些實施例中,個體中與病症相關之症狀或參數之量測降低至少10天。在一些實施例中,個體中與病症相關之症狀或參數之量測降低至少100天。在一些實施例中,病症包含代謝疾病。在一些實施例中,病症包含肝病。Disclosed herein is a method of reducing target mRNA or target protein in an individual in need thereof, comprising administering an effective amount of a pharmaceutical composition of any of the compounds described herein. In some embodiments, the effective amount reduces a measurement of the target mRNA or target protein in the individual relative to a baseline target mRNA or target protein measurement. In some embodiments, the effective amount treats the condition in the individual. In some embodiments, the effective amount reduces a measure of a symptom or parameter associated with the disorder in the individual relative to a baseline symptom or parameter measure. In some embodiments, a measure of a symptom or parameter associated with the condition is reduced in the individual for at least 10 days. In some embodiments, a measure of a symptom or parameter associated with a disorder is reduced in the individual for at least 100 days. In some embodiments, the disorder includes a metabolic disease. In some embodiments, the condition includes liver disease.
本文揭示一種由式(A)或(B)表示之化合物: ; 或其鹽,其中 各w獨立地選自1至20之任何值; 各v獨立地選自1至20之任何值; n選自1至20之任何值; m選自1至20之任何值; z選自1至3之任何值,其中 若z為3,則Y為C, 若z為2,則Y為CR 6,或 若z為1,則Y為C(R 6) 2; Q選自: 視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7 、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中該C 1-6烷基視情況經一或多個獨立地選自鹵素、-CN、-OH、-SH、-NO 2及-NH 2之取代基取代; R 1選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7、-S(O) 2R 7、-OS(O) 2R 7、-OP(O)(OR 7) 2、-OP(S)(OR 7) 2、-SP(O)(OR 7) 2、-OP(O)(SR 7)(OR 7)、-OP(O)(OR 7)N(R 7) 2、-OP(S)(OR 7)N(R 7) 2、-SP(O)(OR 7)N(R 7) 2、-OP(O)(SR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(S)(N(R 7) 2) 2、-SP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-SP(OR 7) 2、-OP(OR 7)(SR 7),-OP(OR 7)N(R 7) 2、-OP(SR 7)N(R 7) 2、-SP(OR 7)N(R 7) 2、-OP(N(R 7) 2) 2及-SP(N(R 7) 2) 2; 各R 2獨立地選自: 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; R 3及R 4各自獨立地選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 5獨立地選自: -OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2; 各R 6獨立地選自: 氫; 鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 7獨立地選自: 氫; C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及 C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。 在一些實施例中,各w獨立地選自1至10之任何值。在一些實施例中,各w獨立地選自1至5之任何值。在一些實施例中,各w為1。在一些實施例中,各v獨立地選自1至10之任何值。在一些實施例中,各v獨立地選自1至5之任何值。在一些實施例中,各v為1。在一些實施例中,n選自1至10之任何值。在一些實施例中,n選自1至5之任何值。在一些實施例中,n為2。在一些實施例中,m選自1至10之任何值。在一些實施例中,m選自1至5之任何值。在一些實施例中,m選自1及2。在一些實施例中,z為3且Y為C。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基。在一些實施例中,Q選自環己基。在一些實施例中,R 1選自-OP(O)(OR 7) 2、-OP(O)(OR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-OP(OR 7)N(R 7) 2及-OP((NR 7) 2) 2。在一些實施例中,R 1選自-OP(O)(OR 7) 2及-OP(OR 7)N(R 7) 2。在一些實施例中,R 1選自-OP(O)(OCH 2CH 3)OH及-OP(OCH 2CH 2CN)N(CH(CH 3) 2) 2。在一些實施例中,R 1為-OP(OCH 2CH 2CN)N(CH(CH 3) 2) 2。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:鹵素、-OR 7、-OC(O)R 7、-SR 7、-N(R 7) 2、-C(O)R 7及-S(O)R 7。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,R 2選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7及-OC(O)R 7。在一些實施例中,R 3選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,R 3選自-OR 7、-SR 7、-OC(O)R 7及-N(R 7) 2。在一些實施例中,R 3選自-OR 7-及-OC(O)R 7。在一些實施例中,R 4選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,R 4選自-OR 7、-SR 7、-OC(O)R 7及-N(R 7) 2。在一些實施例中,R 4選自-OR 7-及-OC(O)R 7。在一些實施例中,R 5選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2及-N(R 7)C(O)OR 7。在一些實施例中,R 5選自-OC(O)R 7及-N(R 7)C(O)R 7。在一些實施例中,各R 7獨立地選自:氫;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,或3至10員雜環。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH及-SH。在一些實施例中,w為1;v為1;n為2;m為1或2;z為3且Y為C;Q為苯基或環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2及C 1-3烷基;R 1選自-OP(O)(OR 7) 2及-OP(OR 7)N(R 7) 2;R 2為經-OH或-OC(O)CH 3取代之C 1烷基;R 3為-OH或-OC(O)CH 3;R 4為-OH或-OC(O)CH 3;及R 5為-NH(O)CH 3。在一些實施例中,化合物包含: 。 This article discloses a compound represented by formula (A) or (B): ; Or a salt thereof, wherein each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20 value; z is selected from any value from 1 to 3, where if z is 3, then Y is C, if z is 2, then Y is CR 6 , or if z is 1, then Y is C(R 6 ) 2 ; Q is selected from: C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 and -NH 2 ; R 1 is selected from: -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C( O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C( O)OR 7 , -OC(O)R 7 , -S(O)R 7 , -S(O) 2 R 7 , -OS(O) 2 R 7 , -OP(O)(OR 7 ) 2 , -OP(S)(OR 7 ) 2 , -SP(O)(OR 7 ) 2 , -OP(O)(SR 7 )(OR 7 ), -OP(O)(OR 7 )N(R 7 ) 2 , -OP(S)(OR 7 )N(R 7 ) 2 , -SP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(SR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(S)(N(R 7 ) 2 ) 2 , -SP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , -SP(OR 7 ) 2 , -OP(OR 7 )(SR 7 ),-OP(OR 7 )N(R 7 ) 2 , -OP(SR 7 )N(R 7 ) 2 , -SP (OR 7 )N(R 7 ) 2 , -OP(N(R 7 ) 2 ) 2 and -SP(N(R 7 ) 2 ) 2 ; each R 2 is independently selected from: Optionally, one or more C 1-6 alkyl substituted with substituents independently selected from the following: halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N( R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N( R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 are each independently selected from: -OR 7 , - SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 ) C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 and -C( O)N(R 7 ) 2 ; each R 6 is independently selected from: hydrogen; halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N (R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and as appropriate, through one or more A C 1-6 alkyl group substituted by a substituent independently selected from the following: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N( R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 7 is independently selected from: Hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring, each of which is independently selected from the following as appropriate by one or more Substituent substitution: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1 -6 alkyl) 2 , -NH (C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic ring, 3 to 10 members Heterocycle, and C 1-6 haloalkyl. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is 1. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is 1. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is 2. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from 1 and 2. In some embodiments, z is 3 and Y is C. In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and - S(O)R 7 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl. In some embodiments, Q is selected from cyclohexyl. In some embodiments, R 1 is selected from -OP(O)(OR 7 ) 2 , -OP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , -OP(OR 7 )N(R 7 ) 2 and -OP((NR 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OR 7 ) 2 and -OP(OR 7 )N(R 7 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OCH 2 CH 3 )OH and -OP(OCH 2 CH 2 CN)N(CH(CH 3 ) 2 ) 2 . In some embodiments, R 1 is -OP(OCH 2 CH 2 CN)N(CH(CH 3 ) 2 ) 2 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: halogen, -OR 7 , -OC(O)R 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 and -S(O)R 7 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 , -OC(O)R 7 , -SR 7 and -N (R 7 ) 2 . In some embodiments, R 2 is selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 and -OC(O)R 7 . In some embodiments, R 3 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, R 3 is selected from -OR 7 , -SR 7 , -OC(O)R 7 and -N(R 7 ) 2 . In some embodiments, R 3 is selected from -OR 7 - and -OC(O)R 7 . In some embodiments, R 4 is selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, R 4 is selected from -OR 7 , -SR 7 , -OC(O)R 7 and -N(R 7 ) 2 . In some embodiments, R 4 is selected from -OR 7 - and -OC(O)R 7 . In some embodiments, R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C (O)N(R 7 ) 2 and -N(R 7 )C(O)OR 7 . In some embodiments, R 5 is selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 . In some embodiments, each R is independently selected from : hydrogen; and optionally C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, or 3 to 10 membered heterocyclic ring. In some embodiments, each R is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl) . In some embodiments, each R 7 is independently selected from C 1-6 alkyl, optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, and -SH. In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each independently modified by one or more Substituted with substituents selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 and C 1-3 alkyl; R 1 is selected from -OP(O)(OR 7 ) 2 and - OP(OR 7 )N(R 7 ) 2 ; R 2 is C 1 alkyl substituted by -OH or -OC(O)CH 3 ; R 3 is -OH or -OC(O)CH 3 ; R 4 is -OH or -OC(O)CH 3 ; and R 5 is -NH(O)CH 3 . In some embodiments, the compound includes: .
交叉參考cross reference
本申請案主張2022年3月16日申請之美國臨時申請案第63/320,431號、2022年6月22日申請之美國臨時申請案第63/354,359號及2022年12月6日申請之美國臨時申請案第63/430,542號之權益,該等申請案以引用之方式併入本文中。 序列表以引用之方式併入 This application proposes U.S. Provisional Application No. 63/320,431 filed on March 16, 2022, U.S. Provisional Application No. 63/354,359 filed on June 22, 2022, and U.S. Provisional Application No. 63/354,359 filed on December 6, 2022. Application No. 63/430,542, which application is incorporated herein by reference. The sequence listing is incorporated by reference.
本申請案與電子格式之序列表一起申請。序列表以在2023年3月13日創建,名為54462-735601_PCT.xml之檔案提供,其大小為922,453位元組。電子格式之序列表中之資訊以全文引用之方式併入。This application is filed together with the sequence listing in electronic format. The sequence listing is provided in a file named 54462-735601_PCT.xml created on March 13, 2023, with a size of 922,453 bytes. The information in the electronic format of the sequence listing is incorporated by reference in its entirety.
N-乙醯基半乳胺糖(GalNAc)為半乳糖之胺糖衍生物。GalNAc及含GalNAc部分可結合凝集素,諸如去唾液酸糖蛋白受體。此等受體可包括於肝細胞上。因此,GalNAc可使寡核苷酸靶向肝細胞或靶向肝臟。N-acetyl galactamine sugar (GalNAc) is an amino sugar derivative of galactose. GalNAc and GalNAc-containing moieties can bind lectins, such as asialoglycoprotein receptors. These receptors may be included on liver cells. Therefore, GalNAc can target oligonucleotides to hepatocytes or to the liver.
本文提供GalNAc部分。此等GalNAc部分可與寡核苷酸(諸如小干擾RNA (siRNA)或反義寡核苷酸(ASO))結合。與GalNAc部分結合之寡核苷酸可投與至個體,靶向肝臟或肝細胞,或用於治療個體之肝臟相關病症。 I. 組合物 This article provides the GalNAc section. These GalNAc moieties can be combined with oligonucleotides such as small interfering RNA (siRNA) or antisense oligonucleotides (ASO). Oligonucleotides that bind to the GalNAc moiety can be administered to an individual to target the liver or hepatocytes, or used to treat liver-related disorders in the individual. I. Composition
在一些實施例中,本文提供組合物,其包含寡核苷酸及N-乙醯基半乳胺糖(GalNAc)部分。在一些實施例中,組合物包含寡核苷酸。寡核苷酸可抑制目標基因或寡核苷酸。寡核苷酸可結合目標寡核苷酸。在一些實施例中,組合物用於本文所描述之方法中。In some embodiments, provided herein are compositions comprising an oligonucleotide and an N-acetylgalactamine sugar (GalNAc) moiety. In some embodiments, the compositions comprise oligonucleotides. Oligonucleotides inhibit the target gene or oligonucleotide. The oligonucleotide binds to the target oligonucleotide. In some embodiments, the compositions are used in the methods described herein.
在一些實施例中,本文提供化合物,其包含寡核苷酸及GalNAc部分。在一些實施例中,化合物包含寡核苷酸。寡核苷酸可與目標寡核苷酸結合。在一些實施例中,化合物用於本文所描述之方法中。在一些實施例中,本文所描述之組合物中包括該化合物。In some embodiments, provided herein are compounds comprising an oligonucleotide and a GalNAc moiety. In some embodiments, the compounds comprise oligonucleotides. The oligonucleotide can bind to the target oligonucleotide. In some embodiments, the compounds are used in the methods described herein. In some embodiments, the compound is included in the compositions described herein.
本文所描述之化合物或組合物之寡核苷酸可包含小干擾RNA (siRNA)或反義寡核苷酸(ASO)。Oligonucleotides of the compounds or compositions described herein may comprise small interfering RNA (siRNA) or antisense oligonucleotides (ASO).
一些實施例包括一種組合物,其包含GalNAc部分,及當以有效量向個體投與時降低個體之細胞、流體或組織中之目標mRNA或蛋白質含量的寡核苷酸。一些實施例包括一種組合物,其包含GalNAc部分,及當以有效量向個體投與時降低肝臟組織中或肝細胞中之目標mRNA或蛋白質含量的寡核苷酸。在一些實施例中,組合物包含GalNAc部分,及當以有效量向個體投與時降低細胞或組織中之目標(例如mRNA)之含量的寡核苷酸。在一些實施例中,細胞為肝細胞。在一些實施例中,組織為肝臟組織。一些實施例包括一種組合物,其包含GalNAc部分,及當以有效量向個體投與時降低肝臟組織中之目標mRNA含量的寡核苷酸。一些實施例包括一種組合物,其包含GalNAc部分,及當以有效量向個體投與時降低肝細胞中之目標mRNA含量的寡核苷酸。Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that, when administered to the subject in an effective amount, reduces the amount of target mRNA or protein in cells, fluids, or tissues of the subject. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that reduces target mRNA or protein levels in liver tissue or in hepatocytes when administered to an individual in an effective amount. In some embodiments, the composition includes a GalNAc moiety, and an oligonucleotide that reduces the amount of a target (eg, mRNA) in a cell or tissue when administered to an individual in an effective amount. In some embodiments, the cells are hepatocytes. In some embodiments, the tissue is liver tissue. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that reduces target mRNA levels in liver tissue when administered to an individual in an effective amount. Some embodiments include a composition comprising a GalNAc moiety and an oligonucleotide that reduces target mRNA levels in hepatocytes when administered to an individual in an effective amount.
在一些實施例中,相對於另一細胞類型,目標寡核苷酸含量之降低對肝細胞具有特異性。在一些實施例中,相對於另一細胞類型,目標RNA含量之降低對肝細胞具有特異性。在一些實施例中,相對於另一細胞類型,目標mRNA含量之降低對肝細胞具有特異性。在一些實施例中,相對於另一細胞類型,目標蛋白含量之降低對肝細胞具有特異性。在一些實施例中,相對於另一組織類型,目標寡核苷酸含量之降低對肝臟組織具有特異性。在一些實施例中,相對於另一組織類型,目標RNA含量之降低對肝臟具有特異性。在一些實施例中,相對於另一組織類型,目標mRNA含量之降低對肝臟具有特異性。在一些實施例中,相對於另一組織類型,目標蛋白含量之降低對肝臟具有特異性。In some embodiments, the reduction in target oligonucleotide content is specific to hepatocytes relative to another cell type. In some embodiments, the reduction in target RNA content is specific to hepatocytes relative to another cell type. In some embodiments, the reduction in target mRNA levels is specific to hepatocytes relative to another cell type. In some embodiments, the reduction in protein of interest is specific to hepatocytes relative to another cell type. In some embodiments, the reduction in target oligonucleotide content is specific to liver tissue relative to another tissue type. In some embodiments, the reduction in target RNA content is specific to liver relative to another tissue type. In some embodiments, the reduction in target mRNA levels is specific to the liver relative to another tissue type. In some embodiments, the reduction in target protein levels is specific to the liver relative to another tissue type.
在一些實施例中,組合物包含GalNAc部分及與目標寡核苷酸結合之寡核苷酸,當以有效量向個體投與時該組合物降低細胞或組織中之目標寡核苷酸含量。在一些實施例中,相較於投與前,目標寡核苷酸含量降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相較於投與前,目標寡核苷酸含量降低約10%或更多。在一些實施例中,相較於投與前,目標寡核苷酸含量降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相較於投與前,目標寡核苷酸含量降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相較於投與前,目標寡核苷酸含量降低不超過約10%。在一些實施例中,相較於投與前,目標寡核苷酸含量降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,目標寡核苷酸含量降低2.5%、5%、7.5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%,或降低由任何兩個前述百分比限定的範圍。In some embodiments, a composition includes a GalNAc moiety and an oligonucleotide that binds to a target oligonucleotide that, when administered to an individual in an effective amount, reduces the target oligonucleotide content in a cell or tissue. In some embodiments, the target oligonucleotide content is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the target oligonucleotide content is reduced by about 10% or more compared to before administration. In some embodiments, the target oligonucleotide content is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% compared to before administration. % or more, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the target oligonucleotide content is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the target oligonucleotide content is reduced by no more than about 10% compared to before administration. In some embodiments, compared to before administration, the target oligonucleotide content decreases by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, No more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the target oligonucleotide content is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or reduce the range defined by any two of the preceding percentages.
在一些實施例中,組合物包含GalNAc部分及與目標mRNA結合之寡核苷酸,當向以有效量個體投與時該組合物降低細胞或組織中之目標mRNA含量。在一些實施例中,相較於投與前,目標mRNA含量降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相較於投與前,目標mRNA含量降低約10%或更多。在一些實施例中,相較於投與前,目標mRNA含量降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相較於投與前,目標mRNA含量降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相較於投與前,目標mRNA含量降低不超過約10%。在一些實施例中,相較於投與前,目標mRNA含量降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,目標mRNA含量降低2.5%、5%、7.5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%,或降低由任何兩個前述百分比限定的範圍。In some embodiments, a composition comprising a GalNAc moiety and an oligonucleotide that binds to a target mRNA reduces the target mRNA content in a cell or tissue when administered to an individual in an effective amount. In some embodiments, the target mRNA content is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the target mRNA content is reduced by about 10% or more compared to before administration. In some embodiments, the target mRNA content is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more compared to before administration. More, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the target mRNA content is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the target mRNA content is reduced by no more than about 10% compared to before administration. In some embodiments, compared to before administration, the target mRNA content decreases by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the target mRNA content is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or reduce the range defined by any two of the preceding percentages.
在一些實施例中,組合物包含GalNAc部分及與編碼目標蛋白之寡核苷酸結合的寡核苷酸,當以有效量向個體投與該組合物時,其降低細胞或組織中之目標蛋白含量。在一些實施例中,細胞為肝細胞。在一些實施例中,組織為肝臟組織。在一些實施例中,相較於投與前,目標蛋白含量降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相較於投與前,目標蛋白含量降低約10%或更多。在一些實施例中,相較於投與前,目標蛋白含量降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相較於投與前,目標蛋白含量降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相較於投與前,目標蛋白含量降低不超過約10%。在一些實施例中,相較於投與前,目標蛋白含量降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,目標蛋白含量降低2.5%、5%、7.5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%,或降低由任何兩個前述百分比限定的範圍。In some embodiments, a composition includes a GalNAc portion and an oligonucleotide bound to an oligonucleotide encoding a protein of interest that, when administered to an individual in an effective amount, reduces the protein of interest in a cell or tissue. content. In some embodiments, the cells are hepatocytes. In some embodiments, the tissue is liver tissue. In some embodiments, the target protein content is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the target protein content is reduced by about 10% or more compared to before administration. In some embodiments, the target protein content is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more compared to before administration. More, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the target protein content is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the target protein content is reduced by no more than about 10% compared to before administration. In some embodiments, the target protein content is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 60% before administration. 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the target protein content is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or reduce the range defined by any two of the preceding percentages.
在一些實施例中,組合物包含GalNAc部分及與目標寡核苷酸(例如mRNA)結合之寡核苷酸,且當以有效量向個體投與時,減少不良表型(例如與目標寡核苷酸相關之病症之症狀)。在一些實施例中,相較於投與前,不良表型減少約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相較於投與前,不良表型減少約10%或更多。在一些實施例中,相較於投與前,不良表型減少約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相較於投與前,不良表型減少不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相較於投與前,不良表型減少不超過約10%。在一些實施例中,相較於投與前,不良表型減少不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,不良表型減少2.5%、5%、7.5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%,或降低由任何兩個前述百分比限定的範圍。In some embodiments, the compositions comprise a GalNAc moiety and an oligonucleotide that binds to a target oligonucleotide (e.g., mRNA) and, when administered to an individual in an effective amount, reduces an undesirable phenotype (e.g., binding to the target oligonucleotide). Symptoms of glycoside-related disorders). In some embodiments, the adverse phenotype is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the adverse phenotype is reduced by about 10% or more compared to before administration. In some embodiments, the adverse phenotype is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more compared to before administration. More, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the adverse phenotype is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the adverse phenotype is reduced by no more than about 10% compared to before administration. In some embodiments, compared to before administration, the adverse phenotype is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the adverse phenotype is reduced by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or reduce the range defined by any two of the preceding percentages.
在一些實施例中,組合物包含GalNAc部分及與目標寡核苷酸(例如mRNA)結合之寡核苷酸,且當以有效量向個體投與時,增加保護性表型(例如能夠預防病症)。在一些實施例中,相較於投與前,保護性表型增加約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相較於投與前,保護性表型增加約10%或更多。在一些實施例中,相較於投與前,保護性表型增加約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%或更多。在一些實施例中,相較於投與前,保護性表型增加約200%或更多、約300%或更多、約400%或更多、約500%或更多、約600%或更多、約700%或更多、約800%或更多、約900%或更多、或約1000%或更多。在一些實施例中,相較於投與前,保護性表型增加不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相較於投與前,保護性表型增加不超過約10%。在一些實施例中,相較於投與前,保護性表型增加不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,相較於投與前,保護性表型增加不超過約200%、不超過約300%、不超過約400%、不超過約500%、不超過約600%、不超過約700%、不超過約800%、不超過約900%或不超過約1000%。在一些實施例中,保護性表型增加2.5%、5%、7.5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、100%、150%、200%、250%、300%、400%、500%、600%、700%、800%、900%或1000%,或增加由任何兩個前述百分比限定的範圍。 A. GalNAc部分及化合物In some embodiments, the compositions comprise a GalNAc moiety and an oligonucleotide that binds to an oligonucleotide of interest (e.g., mRNA) and, when administered to an individual in an effective amount, increases a protective phenotype (e.g., is able to prevent a disorder ). In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 10% or more compared to before administration. In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, compared to before administration. More, about 70% or more, about 80% or more, about 90% or more, or about 100% or more. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, compared to before administration. More, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5% compared to before administration. In some embodiments, the protective phenotype is increased by no more than about 10% compared to before administration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than before administration. About 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than before administration About 700%, no more than about 800%, no more than about 900%, or no more than about 1000%. In some embodiments, the protective phenotype increases by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700% , 800%, 900% or 1000%, or increase the range defined by any two of the preceding percentages. A. GalNAc parts and compounds
在一些實施例中,本文提供組合物,其包含GalNAc部分。在一些實施例中,本文提供組合物,其包含GalNAc部分及寡核苷酸。在一些實施例中,藉由式(I)或式(II)之化合物描述包含GalNAc部分及寡核苷酸之組合物。在一些實施例中,式(I)或式(II)之寡核苷酸為J。在一些實施例中,式(I)或式(II)之GalNAc部分為與J結合之分子部分。寡核苷酸可包含小干擾RNA (siRNA)或反義寡核苷酸(ASO)。In some embodiments, provided herein are compositions comprising a GalNAc moiety. In some embodiments, provided herein are compositions comprising a GalNAc moiety and an oligonucleotide. In some embodiments, compositions comprising a GalNAc moiety and an oligonucleotide are described by compounds of Formula (I) or Formula (II). In some embodiments, the oligonucleotide of Formula (I) or Formula (II) is J. In some embodiments, the GalNAc moiety of Formula (I) or Formula (II) is the moiety of the molecule that binds J. Oligonucleotides may include small interfering RNA (siRNA) or antisense oligonucleotides (ASO).
在一些實施例中,本文提供一種由式(I)或(II)表示之化合物: ; 或其鹽,其中 J為寡核苷酸; 各w獨立地選自1至20之任何值; 各v獨立地選自1至20之任何值; n選自1至20之任何值; m選自1至20之任何值; z選自1至3之任何值,其中 若z為3,則Y為C, 若z為2,則Y為CR 6,或 若z為1,則Y為C(R 6) 2; Q選自: 視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7 、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中該C 1-6烷基視情況經一或多個獨立地選自鹵素、-CN、-OH、-SH、-NO 2及-NH 2之取代基取代; R 1為選自以下之連接子: -O-、-S-、-N(R 7)-、-C(O)-、-C(O)N(R 7)-、-N(R 7)C(O)-、-N(R 7)C(O)N(R 7)-、-OC(O)N(R 7)-、-N(R 7)C(O)O-、-C(O)O-、-OC(O)-、-S(O)-、-S(O) 2-、-OS(O) 2-、-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7-; 各R 2獨立地選自: 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; R 3及R 4各自獨立地選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 5獨立地選自: -OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2; 各R 6獨立地選自: 氫; 鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 7獨立地選自: 氫; C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及 C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。 In some embodiments, provided herein is a compound represented by Formula (I) or (II): ; Or a salt thereof, wherein J is an oligonucleotide; Each w is independently selected from any value from 1 to 20; Each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20; z is selected from any value from 1 to 3, where if z is 3, then Y is C, if z is 2, then Y is CR 6 , or if z is 1, then Y is C(R 6 ) 2 ; Q is selected from: C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C (O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from halogen, -CN, -OH, -SH, -NO 2 and -NH 2 is substituted with a substituent; R 1 is a linker selected from the following: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )-, -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 ) C(O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -OP(O) (OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - ) O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )- and -OPN(R 7 ) 2 NR 7 -; each R 2 is independently selected from: In the case of C 1-6 alkyl substituted with one or more substituents independently selected from the following: halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , - C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 are each independently selected from : -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 ) C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O) OR 7 and -C(O)N(R 7 ) 2 ; each R 6 is independently selected from: hydrogen; halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , - C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , - OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 7 is independently selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each optionally substituted with one or more substituents independently selected from the following: halogen, - CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH (C 1-6 alkyl), C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring, each with one or more as appropriate Substituted with substituents independently selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl , -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 carbon Ring, 3 to 10 membered heterocycle, and C 1-6 haloalkyl.
在一些實施例中,各w獨立地選自1至20之任何值。在一些實施例中,各w獨立地選自1至15之任何值。在一些實施例中,各w獨立地選自1至10之任何值。在一些實施例中,各w獨立地選自1至5之任何值。在一些實施例中,各w獨立地選自1至4之任何值。在一些實施例中,各w獨立地選自1至3之任何值。在一些實施例中,各w獨立地選自1至2之任何值。在一些實施例中,各w獨立地為1。在一些實施例中,w為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, each w is independently selected from any value from 1 to 20. In some embodiments, each w is independently selected from any value from 1 to 15. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is independently selected from any value from 1 to 4. In some embodiments, each w is independently selected from any value from 1 to 3. In some embodiments, each w is independently selected from any value from 1 to 2. In some embodiments, each w is independently 1. In some embodiments, w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,各v獨立地選自1至20之任何值。在一些實施例中,各v獨立地選自1至15之任何值。在一些實施例中,各v獨立地選自1至10之任何值。在一些實施例中,各v獨立地選自1至5之任何值。在一些實施例中,各v獨立地選自1至4之任何值。在一些實施例中,各v獨立地選自1至3之任何值。在一些實施例中,各v獨立地選自1至2之任何值。在一些實施例中,各v獨立地為1。在一些實施例中,v為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, each v is independently selected from any value from 1 to 20. In some embodiments, each v is independently selected from any value from 1 to 15. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is independently selected from any value from 1 to 4. In some embodiments, each v is independently selected from any value from 1 to 3. In some embodiments, each v is independently selected from any value between 1 and 2. In some embodiments, each v is independently 1. In some embodiments, v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,n選自1至20之任何值。在一些實施例中,n選自1至15之任何值。在一些實施例中,n選自1至10之任何值。在一些實施例中,n選自1至9之任何值。在一些實施例中,n選自1至8之任何值。在一些實施例中,n選自1至7之任何值。在一些實施例中,n選自1至6之任何值。在一些實施例中,n選自1至5之任何值。在一些實施例中,n選自1至4之任何值。在一些實施例中,n選自2至4之任何值。在一些實施例中,n選自1至3之任何值。在一些實施例中,n為2或3。在一些實施例中,n為3。在一些實施例中,n選自1至2之任何值。在一些實施例中,n為2。在一些實施例中,n為1。在一些實施例中,n為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, n is selected from any value from 1 to 20. In some embodiments, n is selected from any value from 1 to 15. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 9. In some embodiments, n is selected from any value from 1 to 8. In some embodiments, n is selected from any value from 1 to 7. In some embodiments, n is selected from any value from 1 to 6. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is selected from any value from 1 to 4. In some embodiments, n is selected from any value from 2 to 4. In some embodiments, n is selected from any value from 1 to 3. In some embodiments, n is 2 or 3. In some embodiments, n is 3. In some embodiments, n is selected from any value from 1 to 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,m選自1至20之任何值。在一些實施例中,m選自1至15之任何值。在一些實施例中,m選自1至10之任何值。在一些實施例中,m選自1至9之任何值。在一些實施例中,m選自1至8之任何值。在一些實施例中,m選自1至7之任何值。在一些實施例中,m選自3至7之任何值。在一些實施例中,m選自1至6之任何值。在一些實施例中,m選自2至6之任何值。在一些實施例中,m選自3至6之任何值。在一些實施例中,m選自4至6之任何值。在一些實施例中,m為6。在一些實施例中,m選自1至5之任何值。在一些實施例中,m選自3至5之任何值。在一些實施例中,m為5。在一些實施例中,m為4或5。在一些實施例中,m選自1至4之任何值。在一些實施例中,m為4。在一些實施例中,m為3或4。在一些實施例中,m選自2至4之任何值。在一些實施例中,m選自1至3之任何值。在一些實施例中,m為3。在一些實施例中,m選自1至2之任何值。在一些實施例中,m為2。在一些實施例中,m為1。在一些實施例中,m為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, m is selected from any value from 1 to 20. In some embodiments, m is selected from any value from 1 to 15. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 9. In some embodiments, m is selected from any value from 1 to 8. In some embodiments, m is selected from any value from 1 to 7. In some embodiments, m is selected from any value from 3 to 7. In some embodiments, m is selected from any value from 1 to 6. In some embodiments, m is selected from any value from 2 to 6. In some embodiments, m is selected from any value from 3 to 6. In some embodiments, m is selected from any value from 4 to 6. In some embodiments, m is 6. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from any value from 3 to 5. In some embodiments, m is 5. In some embodiments, m is 4 or 5. In some embodiments, m is selected from any value from 1 to 4. In some embodiments, m is 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from any value from 2 to 4. In some embodiments, m is selected from any value from 1 to 3. In some embodiments, m is 3. In some embodiments, m is selected from any value from 1 to 2. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,z選自1至3之任何值。在一些實施例中,z為3且Y為C。在一些實施例中,z為2且Y為CR 6。在一些實施例中,z為1且Y為C(R 6) 2。 In some embodiments, z is selected from any value from 1 to 3. In some embodiments, z is 3 and Y is C. In some embodiments, z is 2 and Y is CR6 . In some embodiments, z is 1 and Y is C(R 6 ) 2 .
在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中C 1-6烷基視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 3-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中C 1-6烷基視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基、環己基、環戊二烯及環戊基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基。在一些實施例中,Q為苯基。在一些實施例中,Q為環己基。 In some embodiments, Q is selected from C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , - S(O)R 7 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, - NO 2 and -NH 2 . In some embodiments, Q is selected from C 3-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , - S(O)R 7 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, - NO 2 and -NH 2 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and - S(O)R 7 . In some embodiments, Q is selected from C 6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N (R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N (R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S( O)R 7 . In some embodiments, Q is selected from C 5 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N (R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N (R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S( O)R 7 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl, cyclohexyl, cyclopentadiene and cyclopentyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl. In some embodiments, Q is phenyl. In some embodiments, Q is cyclohexyl.
在一些實施例中,R 1為選自以下之連接子:-O-、-S-、-N(R 7)-、-C(O)-、-C(O)N(R 7)-、-N(R 7)C(O)-、-N(R 7)C(O)N(R 7)-、-OC(O)N(R 7)-、-N(R 7)C(O)O-、-C(O)O-、-OC(O)-、-S(O)-、-S(O) 2-、-OS(O) 2-、-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7-。在一些實施例中,R 1為選自以下之連接子:-O-、-S-、-N(R 7)-、-C(O)-、-C(O)N(R 7)-、-N(R 7)C(O)-、-N(R 7)C(O)N(R 7)-、-OC(O)N(R 7)-、-N(R 7)C(O)O-、-C(O)O-、-OC(O)-、-S(O)-、-S(O) 2-、-OS(O) 2-、-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7-。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-、-OP(O)(O -)S-及-OP(OR 7)O-。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(OR 7)O-。在一些實施例中,R 1選自-OP(O)(OR 7)O-及-OP(OR 7)O-。在一些實施例中,R 1為選自以下之連接子:-OP(O)(OH)O-、-SP(O)(OH)O-、-OP(S)(OH)O-、-OP(O)(SH)O-、-OP(O)(OH)S-、-OP(O)(O -)O-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(O)(O -)S-。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-OP(O)(OR 7)NR 7-、-OP(O)(N(R 7) 2)NR 7-、-OP(OR 7)O-、-OP(N(R 7) 2)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2NR 7-。在一些實施例中,R 1選自-S-、-S(O)-、-S(O) 2-、-OS(O) 2、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(O)(OR 7)S-、-SP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(O)(O -)S-。在一些實施例中,R 1選自-S-、-S(O)-、-S(O) 2-、-OS(O) 2、-SP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(SR 7)O-及-OP(O)(OR 7)S-。在一些實施例中,R 1選自-OP(S)(OR 7)O-、-OP(O)(SR 7)O-及-OP(O)(OR 7)S-。在一些實施例中,R 1選自-OP(S)(OR 7)O-、-OP(O)(SR 7)O-、-OP(S)(O -)O-及-OP(O)(S -)O-。在一些實施例中,R 1選自-OP(S)(OR 7)O-及-OP(O)(SR 7)O-。在一些實施例中,R 1選自-OP(O)(OR 7)O-、-OP(OR 7)N(R 7)-及-OPN(R 7) 2O-。在一些實施例中,R 1為-OP(O)(OH)O-、-OP(O)(OCH 2CH 3)O-、-OP(OCH 2CH 2CN)N(CH(CH 3) 2)-或-OPN(CH(CH 3) 2) 2O-。在一些實施例中,R 1選自-OP(O)(OH)O-及OP(O)(O -)O-。在一些實施例中,R 1包含-O-或-S-。在一些實施例中,R 1包含-O-。在一些實施例中,R 1包含-S-。在一些實施例中,R 1為選自以下之連接子:-O-或-S-。在一些實施例中,R 1為-O-。在一些實施例中,R 1為-S-。 In some embodiments, R 1 is a linker selected from: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )- , -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C( O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 ) S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )- and -OPN(R 7 ) 2 NR 7 -. In some embodiments, R 1 is a linker selected from: -O-, -S-, -N(R 7 )-, -C(O)-, -C(O)N(R 7 )- , -N(R 7 )C(O)-, -N(R 7 )C(O)N(R 7 )-, -OC(O)N(R 7 )-, -N(R 7 )C( O)O-, -C(O)O-, -OC(O)-, -S(O)-, -S(O) 2 -, -OS(O) 2 -, -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 ) S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O- , -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O -, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2 NR 7 -. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O )(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)( O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N (R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-and -OPN(R 7 ) 2 NR 7 . In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -SP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O )(SR 7 )O-, -OP(O)(OR 7 )S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S)( O - )O-, -OP(O)(S - )O-, -OP(O)(O - )S-, and -OP(OR 7 )O-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S )(O - )O-, -OP(O)(S - )O- and -OP(OR 7 )O-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O- and -OP(OR 7 )O-. In some embodiments, R 1 is a linker selected from: -OP(O)(OH)O-, -SP(O)(OH)O-, -OP(S)(OH)O-, - OP(O)(SH)O-, -OP(O)(OH)S-, -OP(O)(O - )O-, -SP(O)(O - )O-, -OP(S) (O - )O-, -OP(O)(S - )O- and -OP(O)(O - )S-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -OP(O)(OR 7 )NR 7 -, -OP(O)(N(R 7 ) 2 )NR 7 -, -OP(OR 7 )O-, -OP(N(R 7 ) 2 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2 NR 7 -. In some embodiments, R 1 is selected from -S-, -S(O)-, -S(O) 2 -, -OS(O) 2 , -SP(O)(OR 7 )O-, -OP (S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(O)(OR 7 )S-, -SP(O)(O - )O-, -OP(S )(O - )O-, -OP(O)(S - )O- and -OP(O)(O - )S-. In some embodiments, R 1 is selected from -S-, -S(O)-, -S(O) 2 -, -OS(O) 2 , -SP(O)(OR 7 )O-, -OP (S)(OR 7 )O-, -OP(O)(SR 7 )O-, and -OP(O)(OR 7 )S-. In some embodiments, R 1 is selected from -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, and -OP(O)(OR 7 )S-. In some embodiments, R 1 is selected from -OP(S)(OR 7 )O-, -OP(O)(SR 7 )O-, -OP(S)(O - )O-, and -OP(O )(S - )O-. In some embodiments, R 1 is selected from -OP(S)(OR 7 )O- and -OP(O)(SR 7 )O-. In some embodiments, R 1 is selected from -OP(O)(OR 7 )O-, -OP(OR 7 )N(R 7 )-, and -OPN(R 7 ) 2 O-. In some embodiments, R 1 is -OP(O)(OH)O-, -OP(O)(OCH 2 CH 3 )O-, -OP(OCH 2 CH 2 CN)N(CH(CH 3 ) 2 )-or-OPN(CH(CH 3 ) 2 ) 2 O-. In some embodiments, R 1 is selected from -OP(O)(OH)O- and OP(O)(O - )O-. In some embodiments, R 1 contains -O- or -S-. In some embodiments, R1 includes -O-. In some embodiments, R1 includes -S-. In some embodiments, R1 is a linker selected from: -O- or -S-. In some embodiments, R1 is -O-. In some embodiments, R1 is -S-.
在一些實施例中,各R 2獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:鹵素、-OR 7、-OC(O)R 7、-SR 7、-N(R 7) 2、-C(O)R 7及-S(O)R 7。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1烷基:-OR 7及-OC(O)R 7。在一些實施例中,各R 2獨立地選自-CH 2OH及-CH 2OC(O)CH 3。 In some embodiments, each R 2 is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 7 , -SR 7 , -N( R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N( R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O ) R7 . In some embodiments, each R 2 is independently selected from C 1-3 alkyl substituted with one or more substituents independently selected from: halogen, -OR 7 , -OC(O)R 7 , - SR 7 , -N(R 7 ) 2 , -C(O)R 7 and -S(O)R 7 . In some embodiments, each R 2 is independently selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 2 is independently selected from C 1 alkyl substituted with one or more substituents independently selected from: -OR 7 and -OC(O)R 7 . In some embodiments, each R2 is independently selected from -CH2OH and -CH2OC (O) CH3 .
在一些實施例中,各R 3獨立地選自-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 3獨立地選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 3獨立地選自-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 3獨立地選自-OR 7及-OC(O)R 7。在一些實施例中,R 3獨立地選自-OH及-OC(O)CH 3。 In some embodiments, each R 3 is independently selected from -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , - N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O )OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 3 is independently selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, each R 3 is independently selected from -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 3 is independently selected from -OR 7 and -OC(O)R 7 . In some embodiments, R 3 is independently selected from -OH and -OC(O)CH 3 .
在一些實施例中,各R 4獨立地選自-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 4獨立地選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 4獨立地選自-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 4獨立地選自-OR 7及-OC(O)R 7。在一些實施例中,R 4獨立地選自-OH及-OC(O)CH 3。 In some embodiments, each R 4 is independently selected from -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , - N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O )OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 4 is independently selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, each R 4 is independently selected from -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 4 is independently selected from -OR 7 and -OC(O)R 7 . In some embodiments, R 4 is independently selected from -OH and -OC(O)CH 3 .
在一些實施例中,各R 5獨立地選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2。在一些實施例中,各R 5選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2及-N(R 7)C(O)OR 7。在一些實施例中,各R 5獨立地選自-OC(O)R 7及-N(R 7)C(O)R 7。在一些實施例中,各R 5獨立地選自-N(H)C(O)CH 3。 In some embodiments, each R 5 is independently selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 and -C(O)N(R 7 ) 2 . In some embodiments, each R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 ) C(O)N(R 7 ) 2 and -N(R 7 )C(O)OR 7 . In some embodiments, each R 5 is independently selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 . In some embodiments, each R5 is independently selected from -N(H)C(O) CH3 .
在一些實施例中,各R 6獨立地選自氫、鹵素、-CN、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 6獨立地選自氫、鹵素、-CN -OR 7、-SR 7、-N(R 7) 2及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 6獨立地選自氫、鹵素、-CN、-OH、-SH及-NH 2。 In some embodiments, each R 6 is independently selected from hydrogen, halogen, -CN, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N (R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N (R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and optionally substituted by one or more independently selected from the following C 1-6 alkyl group substituted by: halogen, -CN, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C (O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 6 is independently selected from hydrogen, halogen, -CN -OR 7 , -SR 7 , -N(R 7 ) 2 and optionally via one or more substituents independently selected from: Substituted C 1-6 alkyl: halogen, -OR 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R6 is independently selected from hydrogen, halogen, -CN, -OH, -SH, and -NH2 .
在一些實施例中,各R 7獨立地選自:氫;C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。在一些實施例中,各R 7獨立地選自:氫;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環、3至10員雜環。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。在一些實施例中,R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH及-SH。在一些實施例中,各R 7獨立地選自氫。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代的C 1-3烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。 In some embodiments, each R is independently selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each optionally selected from the group consisting of: one or more Substituent substitution: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH (C 1-6 alkyl), C 3-10 carbocyclic ring, and 3 to 10 membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10 membered heterocyclic ring, Each is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl , -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, and C 1-6 haloalkyl group. In some embodiments, each R is independently selected from : hydrogen; and optionally C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring. In some embodiments, each R is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl) . In some embodiments, R 7 is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, and -SH. In some embodiments, each R is independently selected from hydrogen. In some embodiments, each R is independently selected from C 1-3 alkyl, optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl).
在一些實施例中,w為1;v為1;n為2;m為1或2;z為3且Y為C;Q為苯基或環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2及C 1-3烷基;R 1選自-OP(O)(OR 7)O-、-OP(S)(OR 7)O-、-OP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(OR 7)O-;R 2為經-OH或-OC(O)CH 3取代之C 1烷基;R 3為-OH或-OC(O)CH 3;R 4為-OH或-OC(O)CH 3;及R 5為-NH(O)CH 3。 In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each independently modified by one or more Substituted with substituents selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 and C 1-3 alkyl; R 1 is selected from -OP(O)(OR 7 )O-, -OP(S)(OR 7 )O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O- and -OP (OR 7 )O-; R 2 is C 1 alkyl substituted by -OH or -OC(O)CH 3 ; R 3 is -OH or -OC(O)CH 3 ; R 4 is -OH or -OC (O)CH 3 ; and R 5 is -NH(O)CH 3 .
在一些實施例中,w為1;v為1;n為2;m為1或2;z為3且Y為C;Q為苯基或環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2及C 1-3烷基;R 1選自-OP(O)(OH)O-、-OP(S)(OH)O-、-OP(O)(O -)O-、-OP(S)(O -)O-、-OP(O)(S -)O-及-OP(OH)O-;R 2為經-OH或-OC(O)CH 3取代之C 1烷基;R 3為-OH或-OC(O)CH 3;R 4為-OH或-OC(O)CH 3;及R 5為-NH(O)CH 3。在一些實施例中,w為1;v為1;n為2;m為1或2;z為3且Y為C;Q為苯基或環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2及C 1-3烷基;R 1選自-OP(O)(OH)O-、-OP(S)(OH)O-及-OP(OH)O-;R 2為經-OH或-OC(O)CH 3取代之C 1烷基;R 3為-OH或-OC(O)CH 3;R 4為-OH或-OC(O)CH 3;及R 5為-NH(O)CH 3。 In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each independently modified by one or more Substituted with substituents selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 and C 1-3 alkyl; R 1 is selected from -OP(O)(OH)O-, - OP(S)(OH)O-, -OP(O)(O - )O-, -OP(S)(O - )O-, -OP(O)(S - )O- and -OP(OH )O-; R 2 is C 1 alkyl substituted by -OH or -OC(O)CH 3 ; R 3 is -OH or -OC(O)CH 3 ; R 4 is -OH or -OC(O) CH 3 ; and R 5 is -NH(O)CH 3 . In some embodiments, w is 1; v is 1; n is 2; m is 1 or 2; z is 3 and Y is C; Q is phenyl or cyclohexyl, each independently modified by one or more Substituted with substituents selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 and C 1-3 alkyl; R 1 is selected from -OP(O)(OH)O-, - OP(S)(OH)O- and -OP(OH)O-; R 2 is C 1 alkyl substituted by -OH or -OC(O)CH 3 ; R 3 is -OH or -OC(O) CH 3 ; R 4 is -OH or -OC(O)CH 3 ; and R 5 is -NH(O)CH 3 .
在一些實施例中,式(I)化合物選自: 。 In some embodiments, the compound of formula (I) is selected from: .
在一些實施例中,式(II)化合物選自: 。 In some embodiments, the compound of formula (II) is selected from: .
在一些實施例中,式(I)、(II)或(III)之化合物與凝集素結合。在一些實施例中,化合物與去唾液酸糖蛋白受體結合。在一些實施例中,化合物與肝臟細胞受體結合。在一些實施例中,化合物與肝細胞受體結合。在一些實施例中,化合物靶向肝臟細胞。In some embodiments, compounds of Formula (I), (II) or (III) bind to lectins. In some embodiments, the compound binds to the asialoglycoprotein receptor. In some embodiments, the compounds bind to liver cell receptors. In some embodiments, the compounds bind to hepatocyte receptors. In some embodiments, the compounds target liver cells.
在一些實施例中,本文提供之本文所描述之組合物包含GalNAc化合物。在一些實施例中,GalNAc化合物描述式(A)或式(B)之化合物: ; 或其鹽,其中 各w獨立地選自1至20之任何值; 各v獨立地選自1至20之任何值; n選自1至20之任何值; m選自1至20之任何值; z選自1至3之任何值,其中 若z為3,則Y為C, 若z為2,則Y為CR 6,或 若z為1,則Y為C(R 6) 2; Q選自: 視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7 、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中該C 1-6烷基視情況經一或多個獨立地選自鹵素、-CN、-OH、-SH、-NO 2及-NH 2之取代基取代; R 1選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7、-S(O) 2R 7、-OS(O) 2R 7、-OP(O)(OR 7) 2、-OP(S)(OR 7) 2、-SP(O)(OR 7) 2、-OP(O)(SR 7)(OR 7)、-OP(O)(OR 7)N(R 7) 2、-OP(S)(OR 7)N(R 7) 2、-SP(O)(OR 7)N(R 7) 2、-OP(O)(SR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(S)(N(R 7) 2) 2、-SP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-SP(OR 7) 2、-OP(OR 7)(SR 7),-OP(OR 7)N(R 7) 2、-OP(SR 7)N(R 7) 2、-SP(OR 7)N(R 7) 2、-OP(N(R 7) 2) 2及-SP(N(R 7) 2) 2; 各R 2獨立地選自: 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; R 3及R 4各自獨立地選自: -OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 5獨立地選自: -OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2; 各R 6獨立地選自: 氫; 鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及 視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7; 各R 7獨立地選自: 氫; C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及 C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。 In some embodiments, compositions provided herein and described herein comprise a GalNAc compound. In some embodiments, the GalNAc compound describes a compound of Formula (A) or Formula (B): ; Or a salt thereof, wherein each w is independently selected from any value from 1 to 20; each v is independently selected from any value from 1 to 20; n is selected from any value from 1 to 20; m is selected from any value from 1 to 20 value; z is selected from any value from 1 to 3, where if z is 3, then Y is C, if z is 2, then Y is CR 6 , or if z is 1, then Y is C(R 6 ) 2 ; Q is selected from: C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 and -NH 2 ; R 1 is selected from: -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C( O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C( O)OR 7 , -OC(O)R 7 , -S(O)R 7 , -S(O) 2 R 7 , -OS(O) 2 R 7 , -OP(O)(OR 7 ) 2 , -OP(S)(OR 7 ) 2 , -SP(O)(OR 7 ) 2 , -OP(O)(SR 7 )(OR 7 ), -OP(O)(OR 7 )N(R 7 ) 2 , -OP(S)(OR 7 )N(R 7 ) 2 , -SP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(SR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(S)(N(R 7 ) 2 ) 2 , -SP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , -SP(OR 7 ) 2 , -OP(OR 7 )(SR 7 ),-OP(OR 7 )N(R 7 ) 2 , -OP(SR 7 )N(R 7 ) 2 , -SP (OR 7 )N(R 7 ) 2 , -OP(N(R 7 ) 2 ) 2 and -SP(N(R 7 ) 2 ) 2 ; each R 2 is independently selected from: Optionally, one or more C 1-6 alkyl substituted with substituents independently selected from the following: halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N( R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N( R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; R 3 and R 4 are each independently selected from: -OR 7 , - SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 ) C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 5 is independently selected from: -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 and -C( O)N(R 7 ) 2 ; each R 6 is independently selected from: hydrogen; halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N (R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and as appropriate, through one or more A C 1-6 alkyl group substituted by a substituent independently selected from the following: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N( R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; each R 7 is independently selected from: Hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10-membered heterocyclic ring, each of which is independently selected from the following as appropriate by one or more Substituent substitution: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1 -6 alkyl) 2 , -NH (C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic ring, 3 to 10 members Heterocycle, and C 1-6 haloalkyl.
在一些實施例中,各w獨立地選自1至20之任何值。在一些實施例中,各w獨立地選自1至15之任何值。在一些實施例中,各w獨立地選自1至10之任何值。在一些實施例中,各w獨立地選自1至5之任何值。在一些實施例中,各w獨立地選自1至4之任何值。在一些實施例中,各w獨立地選自1至3之任何值。在一些實施例中,各w獨立地選自1至2之任何值。在一些實施例中,W為1。在一些實施例中,w為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, each w is independently selected from any value from 1 to 20. In some embodiments, each w is independently selected from any value from 1 to 15. In some embodiments, each w is independently selected from any value from 1 to 10. In some embodiments, each w is independently selected from any value from 1 to 5. In some embodiments, each w is independently selected from any value from 1 to 4. In some embodiments, each w is independently selected from any value from 1 to 3. In some embodiments, each w is independently selected from any value from 1 to 2. In some embodiments, W is 1. In some embodiments, w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,各v獨立地選自1至20之任何值。在一些實施例中,各v獨立地選自1至15之任何值。在一些實施例中,各v獨立地選自1至10之任何值。在一些實施例中,各v獨立地選自1至5之任何值。在一些實施例中,各v獨立地選自1至4之任何值。在一些實施例中,各v獨立地選自1至3之任何值。在一些實施例中,各v獨立地選自1至2之任何值。在一些實施例中,各v獨立地為1。在一些實施例中,v為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, each v is independently selected from any value from 1 to 20. In some embodiments, each v is independently selected from any value from 1 to 15. In some embodiments, each v is independently selected from any value from 1 to 10. In some embodiments, each v is independently selected from any value from 1 to 5. In some embodiments, each v is independently selected from any value from 1 to 4. In some embodiments, each v is independently selected from any value from 1 to 3. In some embodiments, each v is independently selected from any value between 1 and 2. In some embodiments, each v is independently 1. In some embodiments, v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,n選自1至20之任何值。在一些實施例中,n選自1至15之任何值。在一些實施例中,n選自1至10之任何值。在一些實施例中,n選自1至9之任何值。在一些實施例中,n選自1至8之任何值。在一些實施例中,n選自1至7之任何值。在一些實施例中,n選自1至6之任何值。在一些實施例中,n選自1至5之任何值。在一些實施例中,n選自1至4之任何值。在一些實施例中,n選自2至4之任何值。在一些實施例中,n選自1至3之任何值。在一些實施例中,n為2或3。在一些實施例中,n為3。在一些實施例中,n選自1至2之任何值。在一些實施例中,n為2。在一些實施例中,n為1。在一些實施例中,n為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, n is selected from any value from 1 to 20. In some embodiments, n is selected from any value from 1 to 15. In some embodiments, n is selected from any value from 1 to 10. In some embodiments, n is selected from any value from 1 to 9. In some embodiments, n is selected from any value from 1 to 8. In some embodiments, n is selected from any value from 1 to 7. In some embodiments, n is selected from any value from 1 to 6. In some embodiments, n is selected from any value from 1 to 5. In some embodiments, n is selected from any value from 1 to 4. In some embodiments, n is selected from any value from 2 to 4. In some embodiments, n is selected from any value from 1 to 3. In some embodiments, n is 2 or 3. In some embodiments, n is 3. In some embodiments, n is selected from any value from 1 to 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,m選自1至20之任何值。在一些實施例中,m選自1至15之任何值。在一些實施例中,m選自1至10之任何值。在一些實施例中,m選自1至9之任何值。在一些實施例中,m選自1至8之任何值。在一些實施例中,m選自1至7之任何值。在一些實施例中,m選自3至7之任何值。在一些實施例中,m選自1至6之任何值。在一些實施例中,m選自2至6之任何值。在一些實施例中,m選自3至6之任何值。在一些實施例中,m選自4至6之任何值。在一些實施例中,m為6。在一些實施例中,m選自1至5之任何值。在一些實施例中,m選自3至5之任何值。在一些實施例中,m為5。在一些實施例中,m為4或5。在一些實施例中,m選自1至4之任何值。在一些實施例中,m為4。在一些實施例中,m為3或4。在一些實施例中,m選自2至4之任何值。在一些實施例中,m選自1至3之任何值。在一些實施例中,m為3。在一些實施例中,m選自1至2之任何值。在一些實施例中,m為2。在一些實施例中,m為1。在一些實施例中,m為1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。In some embodiments, m is selected from any value from 1 to 20. In some embodiments, m is selected from any value from 1 to 15. In some embodiments, m is selected from any value from 1 to 10. In some embodiments, m is selected from any value from 1 to 9. In some embodiments, m is selected from any value from 1 to 8. In some embodiments, m is selected from any value from 1 to 7. In some embodiments, m is selected from any value from 3 to 7. In some embodiments, m is selected from any value from 1 to 6. In some embodiments, m is selected from any value from 2 to 6. In some embodiments, m is selected from any value from 3 to 6. In some embodiments, m is selected from any value from 4 to 6. In some embodiments, m is 6. In some embodiments, m is selected from any value from 1 to 5. In some embodiments, m is selected from any value from 3 to 5. In some embodiments, m is 5. In some embodiments, m is 4 or 5. In some embodiments, m is selected from any value from 1 to 4. In some embodiments, m is 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from any value from 2 to 4. In some embodiments, m is selected from any value from 1 to 3. In some embodiments, m is 3. In some embodiments, m is selected from any value from 1 to 2. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
在一些實施例中,z選自1至3之任何值。在一些實施例中,z為3且Y為C。在一些實施例中,z為2且Y為CR 6。在一些實施例中,z為1且Y為C(R 6) 2。 In some embodiments, z is selected from any value from 1 to 3. In some embodiments, z is 3 and Y is C. In some embodiments, z is 2 and Y is CR6 . In some embodiments, z is 1 and Y is C(R 6 ) 2 .
在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 3-10碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中C 1-6烷基視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 3-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7及C 1-6烷基,其中C 1-6烷基視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 6碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5碳環:鹵素、-CN、-NO 2、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,Q選自視情況經一或多個獨立地選自以下之取代基取代之C 5-6碳環:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基、環己基、環戊二烯及環戊基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2及-NH 2。在一些實施例中,Q選自苯基及環己基。在一些實施例中,Q為苯基。在一些實施例中,Q為環己基。 In some embodiments, Q is selected from C 3-10 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , - S(O)R 7 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, - NO 2 and -NH 2 . In some embodiments, Q is selected from C 3-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , - S(O)R 7 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, - NO 2 and -NH 2 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O )N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and - S(O)R 7 . In some embodiments, Q is selected from C 6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N (R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N (R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, Q is selected from C 5 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -NO 2 , -OR 7 , -SR 7 , -N (R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N (R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, Q is selected from C 5-6 carbocyclic rings optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl, cyclohexyl, cyclopentadiene and cyclopentyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl, each optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2 and -NH 2 . In some embodiments, Q is selected from phenyl and cyclohexyl. In some embodiments, Q is phenyl. In some embodiments, Q is cyclohexyl.
在一些實施例中,R 1選自-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-S(O)R 7、-S(O) 2R 7、-OS(O) 2R 7、-OP(O)(OR 7) 2、-OP(S)(OR 7) 2、-SP(O)(OR 7) 2、-OP(O)(SR 7)(OR 7)、-OP(O)(OR 7)N(R 7) 2、-OP(S)(OR 7)N(R 7) 2、-SP(O)(OR 7)N(R 7) 2、-OP(O)(SR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(S)(N(R 7) 2) 2、-SP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-SP(OR 7) 2、-OP(OR 7)(SR 7)、-OP(OR 7)N(R 7) 2、-OP(SR 7)N(R 7) 2、-SP(OR 7)N(R 7) 2、-OP(N(R 7) 2) 2及-SP(N(R 7) 2) 2。在一些實施例中,R 1選自-OR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7、-OP(O)(OR 7) 2、-OP(O)(OR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(OR 7) 2、OP(OR 7)N(R 7) 2及-OP(N(R 7) 2) 2。在一些實施例中,R 1選自-SR 7、-S(O)R 7、-S(O) 2R 7、-OS(O) 2R 7、-OP(S)(OR 7) 2、-SP(O)(OR 7) 2、-OP(O)(SR 7)(OR 7)、-OP(S)(OR 7)N(R 7) 2、-SP(O)(OR 7)N(R 7) 2、-OP(O)(SR 7)N(R 7) 2、-OP(S)(N(R 7) 2) 2、-SP(O)(N(R 7) 2) 2、-SP(OR 7) 2、-OP(OR 7)(SR 7)、-OP(SR 7)N(R 7) 2、-SP(OR 7)N(R 7) 2及-SP(N(R 7) 2) 2。在一些實施例中,R 1選自-OP(O)(OR 7) 2、-OP(S)(OR 7) 2、-SP(O)(OR 7) 2、-OP(O)(SR 7)(OR 7)、-OP(O)(OR 7)N(R 7) 2、-OP(S)(OR 7)N(R 7) 2、-SP(O)(OR 7)N(R 7) 2、-OP(O)(SR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(S)(N(R 7) 2) 2、-SP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-SP(OR 7) 2、-OP(OR 7)(SR 7)、-OP(OR 7)N(R 7) 2、-OP(SR 7)N(R 7) 2、-SP(OR 7)N(R 7) 2、-OP(N(R 7) 2) 2及-SP(N(R 7) 2) 2。在一些實施例中,R 1選自-OP(O)(OR 7) 2、-OP(O)(OR 7)N(R 7) 2、-OP(O)(N(R 7) 2) 2、-OP(OR 7) 2、-OP(OR 7)N(R 7) 2及-OP((NR 7) 2) 2。在一些實施例中,R 1選自-OP(O)(OR 7) 2及-OP(OR 7)N(R 7) 2。在一些實施例中,R 1選自-OP(O)(OCH 2CH 3)OH及-OP(OCH 2CH 2CN)N(CH(CH 3) 2) 2。在一些實施例中,R 1為-OP(OCH 2CH 2CN)N(CH(CH 3) 2) 2。 In some embodiments, R 1 is selected from -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -S(O)R 7 , -S(O) 2 R 7 , -OS(O) 2 R 7 , -OP(O)(OR 7 ) 2 , -OP(S)(OR 7 ) 2 , -SP(O)(OR 7 ) 2 , -OP(O)(SR 7 )(OR 7 ), -OP(O)(OR 7 )N (R 7 ) 2 , -OP(S)(OR 7 )N(R 7 ) 2 , -SP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(SR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(S)(N(R 7 ) 2 ) 2 , -SP(O)(N(R 7 ) 2 ) 2 ,- OP(OR 7 ) 2 , -SP(OR 7 ) 2 , -OP(OR 7 )(SR 7 ), -OP(OR 7 )N(R 7 ) 2 , -OP(SR 7 )N(R 7 ) 2 , -SP(OR 7 )N(R 7 ) 2 , -OP(N(R 7 ) 2 ) 2 and -SP(N(R 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -OR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C( O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C( O)OR 7 , -OC(O)R 7 , -OP(O)(OR 7 ) 2 , -OP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , OP(OR 7 )N(R 7 ) 2 and -OP(N(R 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -SR 7 , -S(O)R 7 , -S(O) 2 R 7 , -OS(O) 2 R 7 , -OP(S)(OR 7 ) 2 , -SP(O)(OR 7 ) 2 , -OP(O)(SR 7 )(OR 7 ), -OP(S)(OR 7 )N(R 7 ) 2 , -SP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(SR 7 )N(R 7 ) 2 , -OP(S)(N(R 7 ) 2 ) 2 , -SP(O)(N(R 7 ) 2 ) 2 , -SP(OR 7 ) 2 , -OP(OR 7 )(SR 7 ), -OP(SR 7 )N(R 7 ) 2 , -SP(OR 7 )N(R 7 ) 2 and - SP(N(R 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OR 7 ) 2 , -OP(S)(OR 7 ) 2 , -SP(O)(OR 7 ) 2 , -OP(O)(SR 7 )(OR 7 ), -OP(O)(OR 7 )N(R 7 ) 2 , -OP(S)(OR 7 )N(R 7 ) 2 , -SP(O)(OR 7 )N( R 7 ) 2 , -OP(O)(SR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(S)(N(R 7 ) 2 ) 2 , -SP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , -SP(OR 7 ) 2 , -OP(OR 7 )(SR 7 ), -OP(OR 7 )N (R 7 ) 2 , -OP(SR 7 )N(R 7 ) 2 , -SP(OR 7 )N(R 7 ) 2 , -OP(N(R 7 ) 2 ) 2 and -SP(N(R 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OR 7 ) 2 , -OP(O)(OR 7 )N(R 7 ) 2 , -OP(O)(N(R 7 ) 2 ) 2 , -OP(OR 7 ) 2 , -OP(OR 7 )N(R 7 ) 2 and -OP((NR 7 ) 2 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OR 7 ) 2 and -OP(OR 7 )N(R 7 ) 2 . In some embodiments, R 1 is selected from -OP(O)(OCH 2 CH 3 )OH and -OP(OCH 2 CH 2 CN)N(CH(CH 3 ) 2 ) 2 . In some embodiments, R 1 is -OP(OCH 2 CH 2 CN)N(CH(CH 3 ) 2 ) 2 .
在一些實施例中,各R 2獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:鹵素、-OR 7、-OC(O)R 7、-SR 7、-N(R 7) 2、-C(O)R 7及-S(O)R 7。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1-3烷基:-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 2獨立地選自經一或多個獨立地選自以下之取代基取代之C 1烷基:-OR 7及-OC(O)R 7。在一些實施例中,各R 2獨立地選自-CH 2OH及-CH 2OC(O)CH 3。 In some embodiments, each R 2 is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 7 , -SR 7 , -N( R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N( R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O ) R7 . In some embodiments, each R 2 is independently selected from C 1-3 alkyl substituted with one or more substituents independently selected from: halogen, -OR 7 , -OC(O)R 7 , - SR 7 , -N(R 7 ) 2 , -C(O)R 7 and -S(O)R 7 . In some embodiments, each R 2 is independently selected from C 1-3 alkyl substituted with one or more substituents independently selected from: -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 2 is independently selected from C 1 alkyl substituted with one or more substituents independently selected from: -OR 7 and -OC(O)R 7 . In some embodiments, each R 2 is independently selected from -CH 2 OH and -CH 2 OC(O)CH 3 .
在一些實施例中,各R 3獨立地選自-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 3獨立地選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 3獨立地選自-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 3獨立地選自-OR 7及-OC(O)R 7。在一些實施例中,R 3獨立地選自-OH及-OC(O)CH 3。 In some embodiments, each R 3 is independently selected from -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , - N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O )OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 3 is independently selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, each R 3 is independently selected from -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 3 is independently selected from -OR 7 and -OC(O)R 7 . In some embodiments, R 3 is independently selected from -OH and -OC(O)CH 3 .
在一些實施例中,各R 4獨立地選自-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 4獨立地選自鹵素、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 4獨立地選自-OR 7、-OC(O)R 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 4獨立地選自-OR 7及-OC(O)R 7。在一些實施例中,R 4獨立地選自-OH及-OC(O)CH 3。 In some embodiments, each R 4 is independently selected from -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , - N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O )OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 4 is independently selected from halogen, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -OC(O)R 7 and -S( O) R7 . In some embodiments, each R 4 is independently selected from -OR 7 , -OC(O)R 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R 4 is independently selected from -OR 7 and -OC(O)R 7 . In some embodiments, R 4 is independently selected from -OH and -OC(O)CH 3 .
在一些實施例中,各R 5獨立地選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)R 7、-C(O)OR 7及-C(O)N(R 7) 2。在一些實施例中,各R 5選自-OC(O)R 7、-OC(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2及-N(R 7)C(O)OR 7。在一些實施例中,各R 5獨立地選自-OC(O)R 7及-N(R 7)C(O)R 7。在一些實施例中,各R 5獨立地選自-N(H)C(O)CH 3。 In some embodiments, each R 5 is independently selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -N(R 7 )C(O)OR 7 , -C(O)R 7 , -C(O)OR 7 and -C(O)N(R 7 ) 2 . In some embodiments, each R 5 is selected from -OC(O)R 7 , -OC(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 ) C(O)N(R 7 ) 2 and -N(R 7 )C(O)OR 7 . In some embodiments, each R 5 is independently selected from -OC(O)R 7 and -N(R 7 )C(O)R 7 . In some embodiments, each R5 is independently selected from -N(H)C(O) CH3 .
在一些實施例中,各R 6獨立地選自氫、鹵素、-CN、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OR 7、-SR 7、-N(R 7) 2、-C(O)R 7、-C(O)N(R 7) 2、-N(R 7)C(O)R 7、-N(R 7)C(O)N(R 7) 2、-OC(O)N(R 7) 2、-N(R 7)C(O)OR 7、-C(O)OR 7、-OC(O)R 7及-S(O)R 7。在一些實施例中,各R 6獨立地選自氫、鹵素、-CN -OR 7、-SR 7、-N(R 7) 2及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-OR 7、-SR 7及-N(R 7) 2。在一些實施例中,各R 6獨立地選自氫、鹵素、-CN、-OH、-SH及-NH 2。 In some embodiments, each R 6 is independently selected from hydrogen, halogen, -CN, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N (R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N (R 7 )C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 ; and optionally substituted by one or more independently selected from the following C 1-6 alkyl group substituted by: halogen, -CN, -OR 7 , -SR 7 , -N(R 7 ) 2 , -C(O)R 7 , -C(O)N(R 7 ) 2 , -N(R 7 )C(O)R 7 , -N(R 7 )C(O)N(R 7 ) 2 , -OC(O)N(R 7 ) 2 , -N(R 7 )C (O)OR 7 , -C(O)OR 7 , -OC(O)R 7 and -S(O)R 7 . In some embodiments, each R 6 is independently selected from hydrogen, halogen, -CN -OR 7 , -SR 7 , -N(R 7 ) 2 and optionally via one or more substituents independently selected from: Substituted C 1-6 alkyl: halogen, -OR 7 , -SR 7 and -N(R 7 ) 2 . In some embodiments, each R6 is independently selected from hydrogen, halogen, -CN, -OH, -SH, and -NH2 .
在一些實施例中,各R 7獨立地選自:氫;C 1-6烷基、C 2-6烯基及C 2-6炔基,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環,及3至10員雜環;及C 3-10碳環,及3至10員雜環,各自視情況經一或多個獨立地選自以下之取代基取代:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10碳環、3至10員雜環,及C 1-6鹵烷基。在一些實施例中,各R 7獨立地選自:氫;及視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2、-NH(C 1-6烷基)、C 3-10碳環、3至10員雜環。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、=O、=S、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。在一些實施例中,各R 7獨立地選自氫。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-3烷基:鹵素、-CN、-OH、-SH、-NO 2、-NH 2、-O-C 1-6烷基、-S-C 1-6烷基、-N(C 1-6烷基) 2及-NH(C 1-6烷基)。在一些實施例中,各R 7獨立地選自視情況經一或多個獨立地選自以下之取代基取代之C 1-6烷基:鹵素、-CN、-OH及-SH。 In some embodiments, each R is independently selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each optionally selected from the group consisting of: one or more Substituent substitution: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH (C 1-6 alkyl), C 3-10 carbocyclic ring, and 3 to 10 membered heterocyclic ring; and C 3-10 carbocyclic ring, and 3 to 10 membered heterocyclic ring, Each is optionally substituted with one or more substituents independently selected from the following: halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl , -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, and C 1-6 haloalkyl group. In some embodiments, each R is independently selected from : hydrogen; and optionally C 1-6 alkyl substituted with one or more substituents independently selected from: halogen, -CN, -OH, - SH, -NO 2 , -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -NH(C 1- 6 alkyl), C 3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring. In some embodiments, each R is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , =O, =S, -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl) . In some embodiments, each R is independently selected from hydrogen. In some embodiments, each R is independently selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, -SH, -NO 2. -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -N(C 1-6 alkyl) 2 and -NH(C 1-6 alkyl). In some embodiments, each R 7 is independently selected from C 1-6 alkyl, optionally substituted with one or more substituents independently selected from: halogen, -CN, -OH, and -SH.
在一些實施例中,式(A)化合物選自: 。 In some embodiments, the compound of formula (A) is selected from: .
在一些實施例中,本文提供一種由式(B)表示之化合物: 。 In some embodiments, provided herein is a compound represented by Formula (B): .
在一些實施例中,將磷酸酯去質子化以形成式(I)、(II)、(A)或(B)之鹽。在一些實施例中,陽離子為金屬離子,諸如金屬陽離子。金屬陽離子之非限制性實例包括Na +、K +、Mg 2+及Ca 2+。在一些實施例中,金屬陽離子包含Na +。在一些實施例中,金屬陽離子包含K +。在一些實施例中,金屬陽離子包含Mg 2+。在一些實施例中,金屬陽離子包含Ca 2+。在一些實施例中,陽離子為有機或無機小分子。在其中化合物為式(I)或(II)之去質子化形式之一些實施例中,陽離子為寡核苷酸中存在之帶正電核酸。 In some embodiments, the phosphate ester is deprotonated to form a salt of Formula (I), (II), (A) or (B). In some embodiments, the cation is a metal ion, such as a metal cation. Non-limiting examples of metal cations include Na + , K + , Mg 2+ and Ca 2+ . In some embodiments, the metal cation includes Na + . In some embodiments, the metal cation includes K + . In some embodiments, the metal cation includes Mg 2+ . In some embodiments, the metal cation includes Ca 2+ . In some embodiments, the cation is an organic or inorganic small molecule. In some embodiments where the compound is a deprotonated form of Formula (I) or (II), the cation is a positively charged nucleic acid present in the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個額外磷酸酯,或一或多個硫代磷酸酯。J可包括與寡核苷酸連接之一或多個額外磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more additional phosphates, or one or more phosphorothioates, linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個額外磷酸酯,或一或多個硫代磷酸酯。J可包括與寡核苷酸連接之一或多個額外磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more additional phosphates, or one or more phosphorothioates, linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個磷酸酯或硫代磷酸酯。J可包括與寡核苷酸連接之一或多個磷酸酯。J可包括一個與寡核苷酸連接之磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。J可包括一個與寡核苷酸連接之硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include a phosphate linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include a phosphorothioate linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。此化合物中與寡核苷酸(J)連接之結構為GalNAc部分之實例。J可包括與寡核苷酸連接之一或多個磷酸酯或硫代磷酸酯。J可包括與寡核苷酸連接之一或多個磷酸酯。J可包括一個與寡核苷酸連接之磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。J可包括一個與寡核苷酸連接之硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . The structure linked to oligonucleotide (J) in this compound is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include a phosphate linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include a phosphorothioate linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個額外磷酸酯,或一或多個硫代磷酸酯。J可包括與寡核苷酸連接之一或多個額外磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more additional phosphates, or one or more phosphorothioates, linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個額外磷酸酯,或一或多個硫代磷酸酯。J可包括與寡核苷酸連接之一或多個額外磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more additional phosphates, or one or more phosphorothioates, linked to the oligonucleotide. J may include one or more additional phosphates linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。J可包括與寡核苷酸連接之一或多個磷酸酯或硫代磷酸酯。J可包括與寡核苷酸連接之一或多個磷酸酯。J可包括一個與寡核苷酸連接之磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。J可包括一個與寡核苷酸連接之硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . J may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include a phosphate linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include a phosphorothioate linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。此化合物中與寡核苷酸(J)連接之結構可稱為「ETL17」,且為GalNAc部分之實例。J可包括與寡核苷酸連接之一或多個磷酸酯或硫代磷酸酯。J可包括與寡核苷酸連接之一或多個磷酸酯。J可包括一個與寡核苷酸連接之磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。J可包括一個與寡核苷酸連接之硫代磷酸酯。 Some embodiments include the following, where J is an oligonucleotide: . The structure linked to oligonucleotide (J) in this compound may be termed "ETL17" and is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include a phosphate linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include a phosphorothioate linked to the oligonucleotide.
一些實施例包括以下各者,其中J為寡核苷酸: 。此化合物中與寡核苷酸(J)連接之結構為GalNAc部分之實例。J可包括與寡核苷酸連接之一或多個磷酸酯或硫代磷酸酯。J可包括與寡核苷酸連接之一或多個磷酸酯。J可包括一個與寡核苷酸連接之磷酸酯。J可包括與寡核苷酸連接之一或多個硫代磷酸酯。J可包括一個與寡核苷酸連接之硫代磷酸酯。在任何實施例中,J可包括額外連接子。 1. 類似物 Some embodiments include the following, where J is an oligonucleotide: . The structure linked to oligonucleotide (J) in this compound is an example of a GalNAc moiety. J may include one or more phosphates or phosphorothioates linked to the oligonucleotide. J may include one or more phosphates linked to the oligonucleotide. J may include a phosphate linked to the oligonucleotide. J may include one or more phosphorothioates linked to the oligonucleotide. J may include a phosphorothioate linked to the oligonucleotide. In any embodiment, J may include additional linkers. 1. Analogues
具有碳-碳雙鍵或碳-氮雙鍵之化學實體可以 Z或 E形式(或順式或反式形式)存在。此外,一些化學實體可以各種互變異構形式存在。除非另外規定,否則本文所描述之化合物亦意欲包括所有 Z、 E及互變異構形式。 Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds may exist in the Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are also intended to include all Z , E , and tautomeric forms.
「互變異構物」係指其中質子有可能自分子之一個原子移位至同一分子之另一原子的分子或部分。在某些實施例中,本文中所展現之化合物以互變異構物形式存在。在其中可能發生互變異構化之情形中,將存在互變異構物之化學平衡。互變異構物之確切比率視若干因素而定,包括物理狀態、溫度、溶劑及pH。互變異構平衡之一些實例包括: 。 "Tautomer" refers to a molecule or part of a molecule in which it is possible for a proton to be displaced from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomeric forms. In situations where tautomerization may occur, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent and pH. Some examples of tautomeric equilibrium include: .
在一些實施例中,本文揭示之化合物及部分以不同的富集同位素形式使用,例如富集 2H、 3H、 11C、 13C及/或 14C之含量。在一個特定實施例中,化合物在至少一個位置經氘化。可藉由美國專利第5,846,514號及第6,334,997號中描述之程序,來製備此類氘化形式。如美國專利第5,846,514號及第6,334,997號中所描述,氘化可改良代謝穩定性及/或功效,因此增加藥物作用之持續時間。 In some embodiments, the compounds and moieties disclosed herein are used in different isotopically enriched forms, such as enriched in 2H , 3H , 11C , 13C and/or 14C content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and/or efficacy, thereby increasing the duration of drug action.
除非另外陳述,否則本文所描述之化合物及部分意欲包括區別僅在於存在一或多個經同位素富集原子的化合物及部分。舉例而言,具有本發明結構,但其中氫經氘或氚置換或碳經 13C或 14C富集碳置換的化合物屬於本發明之範疇內。 Unless otherwise stated, the compounds and moieties described herein are intended to include compounds and moieties that differ solely in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention, but in which the hydrogen is replaced by deuterium or tritium or the carbon is replaced by a 13 C or 14 C rich carbon, are within the scope of the present invention.
本發明之化合物及部分視情況在構成此類化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言,化合物可用同位素,諸如氘( 2H)、氚( 3H)、碘-125 ( 125I)或碳-14 ( 14C)標記。經 2H、 11C、 13C、 14C、 15C、 12N、 13N、 15N、 16N、 16O、 17O、 14F、 15F、 16F、 17F、 18F、 33S、 34S、 35S、 36S、 35Cl、 37Cl、 79Br、 81Br及 125I同位素取代均涵蓋在內。本發明之化合物及部分之所有同位素變體無論是否具放射性均涵蓋在本發明之範疇內。 The compounds and portions of the invention optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, compounds can be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Via 2H , 11C , 13C , 14C , 15C , 12N , 13N , 15N , 16N , 16O , 17O , 14F , 15F , 16F , 17F , 18F , 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br and 125 I isotope substitutions are covered. All isotopic variations of the compounds and moieties of the invention, whether or not radioactive, are included within the scope of the invention.
在某些實施例中,本文所揭示之化合物及部分中之一些或全部 1H原子經 2H原子置換。合成含氘化合物之方法為此項技術中已知的,且包括(僅作為非限制性實例)以下合成方法。 In certain embodiments, some or all of the 1 H atoms in the compounds and moieties disclosed herein are replaced with 2 H atoms. Methods of synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
使用諸如描述於以下中之各種方法來合成氘取代的化合物:Dean, Dennis C.編. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 第110頁;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;及Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32。Deuterium-substituted compounds are synthesized using various methods such as those described in: Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, page 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony . Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
氘化起始材料可輕易地獲得,且進行本文所描述之合成方法以提供含氘化合物之合成。大量含氘試劑及建構嵌段可購自化學供應商,諸如Aldrich Chemical Co.。Deuterated starting materials are readily available and the synthetic methods described herein are performed to provide the synthesis of deuterium-containing compounds. A wide variety of deuterium-containing reagents and building blocks are available from chemical suppliers such as Aldrich Chemical Co.
本發明中包括本文所描述之化合物之鹽,尤其醫藥學上可接受之鹽。具有足夠酸性、足夠鹼性或兩種官能基的本發明之化合物可以與多種無機鹼以及無機酸及有機酸中之任一種反應形成鹽。或者,本身帶電荷之化合物,諸如具有四級氮者,能夠與適當相對離子形成鹽,該相對離子例如鹵離子,諸如溴離子、氯離子或氟離子,特別地溴離子。Included in the present invention are salts of the compounds described herein, especially pharmaceutically acceptable salts. Compounds of the present invention having sufficiently acidic, sufficiently basic, or both functional groups can react with a variety of inorganic bases as well as any of inorganic and organic acids to form salts. Alternatively, compounds that are inherently charged, such as those with quaternary nitrogen, can form salts with appropriate counter ions, such as halide ions, such as bromide, chloride or fluoride, in particular bromide.
在一些情況下,本文所描述之化合物可以非鏡像異構物、鏡像異構物或其他立體異構形式存在。本文所呈現之化合物包括所有非鏡像異構、鏡像異構及差向異構形式以及其適當混合物。立體異構物之分離可藉由層析或藉由形成非鏡像異構物及藉由再結晶或層析分離或其任何組合來執行。(Jean Jacques, Andre Collet, Samuel H. Wilen, 「Enantiomers, Racemates and Resolutions」, John Wiley And Sons, Inc., 1981,該揭示以引用的方式併入本文中)。立體異構物亦可藉由立體選擇性合成獲得。In some cases, the compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomers, enantiomers and epimeric forms as well as appropriate mixtures thereof. Separation of stereoisomers can be performed by chromatography or by formation of diastereomers and by recrystallization or chromatographic separation or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981, which disclosure is incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.
本文所描述之方法及組合物包括使用非晶形式以及結晶形式(亦稱為多形體)。本文所描述之化合物可呈醫藥學上可接受之鹽形式。在一些實施例中,具有相同類型活性之此等化合物之活性代謝物亦包括在本發明之範疇內。另外,本文所描述之化合物可以非溶劑化或與醫藥學上可接受之溶劑(諸如水、乙醇及其類似者)一起溶劑化形式存在。本文中所呈現之化合物之溶劑化形式亦視為揭示於本文中。 B. 寡核苷酸 The methods and compositions described herein include the use of amorphous as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. In some embodiments, active metabolites of these compounds that possess the same type of activity are also included within the scope of the invention. Additionally, the compounds described herein may exist in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solved forms of the compounds presented herein are also deemed to be disclosed herein. B. Oligonucleotide
在一些實施例中,本文提供包含寡核苷酸之組合物或化合物。該寡核苷酸可與GalNAc部分結合。該寡核苷酸可直接連接至與GalNAc部分連接之連接子。該寡核苷酸可用於本文所描述之方法中。In some embodiments, provided herein are compositions or compounds comprising oligonucleotides. This oligonucleotide can bind to the GalNAc moiety. The oligonucleotide can be directly linked to a linker linked to the GalNAc moiety. Such oligonucleotides can be used in the methods described herein.
在一些實施例中,該寡核苷酸與目標寡核苷酸結合。目標寡核苷酸之實例包括目標RNA或目標DNA。在一些實施例中,該寡核苷酸與目標DNA結合。在一些實施例中,該寡核苷酸與目標DNA結合,且抑制目標DNA表現RNA (例如mRNA)。在一些實施例中,該寡核苷酸與目標RNA結合。目標RNA可包括目標mRNA。在一些實施例中,該寡核苷酸與目標mRNA結合。在一些實施例中,該寡核苷酸抑制目標mRNA,諸如減少目標mRNA之量、引起目標mRNA降解、或減少或防止目標mRNA轉譯。在一些實施例中,該寡核苷酸減少目標mRNA產生之目標蛋白之量,例如藉由抑制目標mRNA。該寡核苷酸可包括小干擾RNA (siRNA)。該寡核苷酸可包括反義寡核苷酸(ASO)。In some embodiments, the oligonucleotide binds to a target oligonucleotide. Examples of target oligonucleotides include target RNA or target DNA. In some embodiments, the oligonucleotide binds to target DNA. In some embodiments, the oligonucleotide binds to target DNA and inhibits expression of RNA (eg, mRNA) from the target DNA. In some embodiments, the oligonucleotide binds to target RNA. Target RNA may include target mRNA. In some embodiments, the oligonucleotide binds to target mRNA. In some embodiments, the oligonucleotide inhibits the target mRNA, such as reducing the amount of the target mRNA, causing degradation of the target mRNA, or reducing or preventing translation of the target mRNA. In some embodiments, the oligonucleotide reduces the amount of target protein produced by the target mRNA, for example, by inhibiting the target mRNA. The oligonucleotide may include small interfering RNA (siRNA). The oligonucleotides may include antisense oligonucleotides (ASO).
在一些實施例中,組合物包含與目標寡核苷酸結合且抑制由目標寡核苷酸編碼之目標蛋白表現的寡核苷酸。在一些實施例中,組合物包含與目標RNA結合且抑制由目標RNA編碼之目標蛋白表現的寡核苷酸。在一些實施例中,組合物包含與目標mRNA結合且抑制由目標mRNA編碼之目標蛋白表現的寡核苷酸。In some embodiments, the composition includes an oligonucleotide that binds to a target oligonucleotide and inhibits expression of a target protein encoded by the target oligonucleotide. In some embodiments, the composition includes an oligonucleotide that binds to a target RNA and inhibits expression of a target protein encoded by the target RNA. In some embodiments, the composition includes an oligonucleotide that binds to a target mRNA and inhibits expression of a target protein encoded by the target mRNA.
在一些實施例中,組合物包含與目標寡核苷酸結合且抑制由目標寡核苷酸編碼之第二寡核苷酸表現的寡核苷酸。在一些實施例中,組合物包含與目標DNA結合且抑制由目標DNA編碼之目標RNA表現的寡核苷酸。在一些實施例中,組合物包含與目標DNA結合且抑制由目標DNA編碼之目標mRNA表現的寡核苷酸。In some embodiments, the composition includes an oligonucleotide that binds to a target oligonucleotide and inhibits the expression of a second oligonucleotide encoded by the target oligonucleotide. In some embodiments, the compositions comprise oligonucleotides that bind to target DNA and inhibit expression of target RNA encoded by the target DNA. In some embodiments, the compositions comprise oligonucleotides that bind to target DNA and inhibit expression of target mRNA encoded by the target DNA.
目標寡核苷酸可藉由多種方式鑑別。在一些情況下,目標寡核苷酸包含表現量與病症(例如肝病)發生相關之mRNA。在一些情況下,目標寡核苷酸包含由具有與病症相關之特定基因型之基因編碼的mRNA。大規模人類遺傳資料可改善醫藥發現及研發之成功率。全基因體關聯研究(Genome Wide Association Study;GWAS)可偵測群體樣本中之基因變異體與性狀之間的相關性。GWAS可實現對疾病之生物學之較佳理解,且提供可應用的治療。GWAS可利用基因分型及/或定序資料,且通常涉及評估在基因體上相對均勻分佈之數百萬基因變異體。最常見GWAS設計為病例對照研究,其涉及在病例對比對照中比較變異體頻率。若變異體在病例對比對照中具有顯著不同的頻率,則該變異體稱為與疾病相關。可用於GWAS中之相關性統計量為p值,作為統計顯著性之量測;勝算比(odds ratio;OR),作為效應大小之量測;或β (beta)係數,作為效應大小之量測。研究人員通常假設相加性遺傳模型且計算等位基因勝算比,其為等位基因之各額外複本所賦予的疾病之風險增加(或降低) (相較於不攜帶該等位基因之複本)。GWAS之設計及解釋中的額外概念為連鎖不平衡,其為等位基因之非隨機關聯。連鎖不平衡之存在可混淆哪一變異體為「致因性的」。Target oligonucleotides can be identified in a variety of ways. In some cases, the target oligonucleotides comprise mRNA that expresses amounts associated with the development of a disorder (eg, liver disease). In some cases, the target oligonucleotide includes mRNA encoded by a gene having a specific genotype associated with a disorder. Large-scale human genetic data can improve the success of medical discovery and development. Genome Wide Association Study (GWAS) can detect the correlation between genetic variants and traits in population samples. GWAS can lead to a better understanding of the biology of disease and provide applicable treatments. GWAS can utilize genotyping and/or sequencing data and typically involve the evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is a case-control study, which involves comparing variant frequencies in cases versus controls. A variant is said to be associated with a disease if it has a significantly different frequency in cases versus controls. Correlation statistics that can be used in GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta (beta) coefficients, as a measure of effect size. . Researchers typically assume an additive genetic model and calculate the allelic odds ratio, which is the increased (or decreased) risk of a disease conferred by each additional copy of an allele (compared to a copy that does not carry that allele). . An additional concept in the design and interpretation of GWAS is linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can confuse which variant is "causative."
變異體之功能註解及/或濕式實驗室實驗可鑑別出經由GWAS鑑別之致因性遺傳變異體,且在許多情況下可引起致病基因之鑑別。特別地,理解致因性遺傳變異體之功能效應(例如,蛋白質功能損失、蛋白質功能獲得、基因表現增加或基因表現降低)可允許變異體用作用於目標基因之治療調節的代理,或進一步理解調節該目標之療法的潛在治療功效及安全性。Functional annotation of variants and/or wet laboratory experiments can identify causative genetic variants identified through GWAS and, in many cases, lead to the identification of disease-causing genes. In particular, understanding the functional effects of a causative genetic variant (e.g., protein loss of function, protein gain of function, increased gene expression, or decreased gene expression) may allow the variant to be used as an agent for therapeutic modulation of a target gene, or to further understand Potential therapeutic efficacy and safety of therapies that modulate this target.
此類基因-疾病關聯之鑑別已提供對疾病生物學之見解且可用於鑑別醫藥行業之新穎治療目標。為了轉換衍生自人類遺傳學之治療見解,患者之疾病生物學可經外源地『程式化』為複製來自人類遺傳學之觀測。治療模態存在若干潛在選項,其可使經由人類遺傳學鑑別之治療性目標轉換為新穎藥品。此等可包括諸如小分子及單株抗體之公認的治療模態、諸如寡核苷酸之成熟化模態、及諸如基因療法及基因編輯之新興模態。治療模態之選擇可視若干因素而定,包括目標之位置(例如細胞內、細胞外或分泌性)、相關組織(例如肝臟)及相關適應症。可進行此類研究以藉由本文所描述之組合物或化合物鑑別用於siRNA或ASO抑制的特定肝病相關之目標。The identification of such gene-disease associations has provided insights into disease biology and can be used to identify novel therapeutic targets for the pharmaceutical industry. To translate therapeutic insights derived from human genetics, the patient's disease biology can be exogenously "programmed" to replicate observations derived from human genetics. Several potential options exist for therapeutic modalities that could transform therapeutic targets identified through human genetics into novel pharmaceuticals. These may include established therapeutic modalities such as small molecules and monoclonal antibodies, established modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of treatment modality will depend on several factors, including the location of the target (eg, intracellular, extracellular, or secretory), the tissue of interest (eg, liver), and the associated indications. Such studies can be performed to identify specific liver disease-related targets for siRNA or ASO inhibition by the compositions or compounds described herein.
一些實施例包括使用本文揭示之方法製備寡核苷酸或siRNA之方法。舉例而言,可使用包括合成步驟之本文中之實例的任何態樣。一些實施例包括製備GalNAc部分或製備具有GalNAc部分之寡核苷酸。 1. siRNA Some embodiments include methods of preparing oligonucleotides or siRNA using the methods disclosed herein. For example, any aspect of the examples herein including synthetic steps may be used. Some embodiments include making a GalNAc moiety or making an oligonucleotide having a GalNAc moiety. 1. siRNA
在一些實施例中,組合物包含與目標寡核苷酸(例如mRNA)結合之寡核苷酸,其中該寡核苷酸包含小干擾RNA (siRNA)。在一些實施例中,組合物包含與目標寡核苷酸(例如mRNA)結合之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股之siRNA。在一些實施例中,有義股包含RNA。在一些實施例中,反義股包含RNA。In some embodiments, the composition includes an oligonucleotide that binds to a target oligonucleotide (eg, mRNA), wherein the oligonucleotide includes small interfering RNA (siRNA). In some embodiments, the compositions comprise oligonucleotides that bind to a target oligonucleotide (eg, mRNA), wherein the oligonucleotides comprise siRNA containing a sense strand and an antisense strand. In some embodiments, the sense strand comprises RNA. In some embodiments, the antisense strands comprise RNA.
在一些實施例中,有義股之長度為12-30個核苷。在一些實施例中,有義股之長度為14-30個核苷。在一些實施例中,有義股之長度為至少約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,有義股之長度為至少12個核苷酸。在一些實施例中,有義股之長度為至少14個核苷酸。在一些實施例中,有義股之長度為至少16個核苷酸。在一些實施例中,有義股之長度為至少18個核苷酸。在一些實施例中,有義股之長度為至少20個核苷酸。在一些實施例中,有義股之長度為至少22個核苷酸。在一些實施例中,有義股之長度為至少24個核苷酸。在一些實施例中,有義股之長度為至少26個核苷酸。在一些實施例中,有義股之長度為至少28個核苷酸。在一些實施例中,有義股之長度為至少30個核苷酸。在一些實施例中,有義股之長度為不超過約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,有義股之長度為不超過12個核苷酸。在一些實施例中,有義股之長度為不超過14個核苷酸。在一些實施例中,有義股之長度為不超過16個核苷酸。在一些實施例中,有義股之長度為不超過18個核苷酸。在一些實施例中,有義股之長度為不超過20個核苷酸。在一些實施例中,有義股之長度為不超過22個核苷酸。在一些實施例中,有義股之長度為不超過24個核苷酸。在一些實施例中,有義股之長度為不超過26個核苷酸。在一些實施例中,有義股之長度為不超過28個核苷酸。在一些實施例中,有義股之長度為不超過30個核苷酸。In some embodiments, the sense strand is 12-30 nucleotides in length. In some embodiments, the sense strand is 14-30 nucleotides in length. In some embodiments, the length of the sense strands is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleosides. In some embodiments, the sense strand is at least 12 nucleotides in length. In some embodiments, the sense strand is at least 14 nucleotides in length. In some embodiments, the sense strand is at least 16 nucleotides in length. In some embodiments, the sense strand is at least 18 nucleotides in length. In some embodiments, the sense strand is at least 20 nucleotides in length. In some embodiments, the sense strand is at least 22 nucleotides in length. In some embodiments, the sense strand is at least 24 nucleotides in length. In some embodiments, the sense strand is at least 26 nucleotides in length. In some embodiments, the sense strand is at least 28 nucleotides in length. In some embodiments, the sense strand is at least 30 nucleotides in length. In some embodiments, the length of the sense strands is no more than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29 or 30 nucleosides. In some embodiments, the sense strand is no more than 12 nucleotides in length. In some embodiments, the sense strand is no more than 14 nucleotides in length. In some embodiments, the sense strand is no more than 16 nucleotides in length. In some embodiments, the sense strand is no more than 18 nucleotides in length. In some embodiments, the sense strand is no more than 20 nucleotides in length. In some embodiments, the sense strand is no more than 22 nucleotides in length. In some embodiments, the sense strand is no more than 24 nucleotides in length. In some embodiments, the sense strand is no more than 26 nucleotides in length. In some embodiments, the sense strand is no more than 28 nucleotides in length. In some embodiments, the sense strand is no more than 30 nucleotides in length.
在一些實施例中,反義股之長度為12-30個核苷。在一些實施例中,反義股之長度為14-30個核苷。在一些實施例中,反義股之長度為至少約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,反義股之長度為至少12個核苷酸。在一些實施例中,反義股之長度為至少14個核苷酸。在一些實施例中,反義股之長度為至少16個核苷酸。在一些實施例中,反義股之長度為至少18個核苷酸。在一些實施例中,反義股之長度為至少20個核苷酸。在一些實施例中,反義股之長度為至少22個核苷酸。在一些實施例中,反義股之長度為至少24個核苷酸。在一些實施例中,反義股之長度為至少26個核苷酸。在一些實施例中,反義股之長度為至少28個核苷酸。在一些實施例中,反義股之長度為至少30個核苷酸。在一些實施例中,反義股之長度為不超過約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,反義股之長度為不超過12個核苷酸。在一些實施例中,反義股之長度為不超過14個核苷酸。在一些實施例中,反義股之長度為不超過16個核苷酸。在一些實施例中,反義股之長度為不超過18個核苷酸。在一些實施例中,反義股之長度為不超過20個核苷酸。在一些實施例中,反義股之長度為不超過22個核苷酸。在一些實施例中,反義股之長度為不超過24個核苷酸。在一些實施例中,反義股之長度為不超過26個核苷酸。在一些實施例中,反義股之長度為不超過28個核苷酸。在一些實施例中,反義股之長度為不超過30個核苷酸。在一些實施例中,反義股與有義股具有相同長度。In some embodiments, the antisense strand is 12-30 nucleotides in length. In some embodiments, the antisense strand is 14-30 nucleotides in length. In some embodiments, the length of the antisense strand is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleosides. In some embodiments, the antisense strand is at least 12 nucleotides in length. In some embodiments, the antisense strand is at least 14 nucleotides in length. In some embodiments, the antisense strand is at least 16 nucleotides in length. In some embodiments, the antisense strand is at least 18 nucleotides in length. In some embodiments, the antisense strand is at least 20 nucleotides in length. In some embodiments, the antisense strand is at least 22 nucleotides in length. In some embodiments, the antisense strand is at least 24 nucleotides in length. In some embodiments, the antisense strand is at least 26 nucleotides in length. In some embodiments, the antisense strand is at least 28 nucleotides in length. In some embodiments, the antisense strand is at least 30 nucleotides in length. In some embodiments, the length of the antisense strand is no more than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29 or 30 nucleosides. In some embodiments, the antisense strand is no more than 12 nucleotides in length. In some embodiments, the antisense strand is no more than 14 nucleotides in length. In some embodiments, the antisense strand is no more than 16 nucleotides in length. In some embodiments, the antisense strand is no more than 18 nucleotides in length. In some embodiments, the antisense strand is no more than 20 nucleotides in length. In some embodiments, the antisense strand is no more than 22 nucleotides in length. In some embodiments, the antisense strand is no more than 24 nucleotides in length. In some embodiments, the antisense strand is no more than 26 nucleotides in length. In some embodiments, the antisense strand is no more than 28 nucleotides in length. In some embodiments, the antisense strand is no more than 30 nucleotides in length. In some embodiments, the antisense strand is the same length as the sense strand.
在一些實施例中,組合物包含抑制目標寡核苷酸(例如mRNA)之表現之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股之siRNA,其中有義股之長度為12-30個核苷。在一些實施例中,組合物包含長度為如下之有義股:10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷,或由任何兩個前述數目限定的範圍。在一些實施例中,組合物包含長度為12-30個核苷之反義股。在一些實施例中,組合物包含長度為如下之反義股:10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷,或由任何兩個前述數目限定的範圍。In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target oligonucleotide (eg, mRNA), wherein the oligonucleotide comprises an siRNA containing a sense strand and an antisense strand, wherein the sense strand 12-30 nucleosides in length. In some embodiments, the composition includes sense strands of lengths: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29 or 30 nucleosides, or a range limited by any two of the foregoing numbers. In some embodiments, the compositions comprise antisense strands that are 12-30 nucleosides in length. In some embodiments, the composition includes antisense strands of length: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29 or 30 nucleosides, or a range limited by any two of the foregoing numbers.
在一些實施例中,組合物包含抑制目標寡核苷酸(例如mRNA)之表現之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股的siRNA,各股之長度獨立地為約14-30個核苷,且有義股及反義股中之至少一者包含含有全長人類目標mRNA序列之約12-30個連續核苷的核苷序列。在一些實施例中,有義股及反義股中之至少一者包含含有全長人類目標mRNA序列中之一者之至少約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或更多個連續核苷的核苷序列。In some embodiments, the compositions comprise oligonucleotides that inhibit the expression of a target oligonucleotide (e.g., mRNA), wherein the oligonucleotides comprise siRNA containing a sense strand and an antisense strand, each strand being of independent length. The base is about 14-30 nucleotides, and at least one of the sense strand and the antisense strand comprises a nucleotide sequence of about 12-30 contiguous nucleotides that contains the full-length human target mRNA sequence. In some embodiments, at least one of the sense strand and the antisense strand comprises at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, A nucleoside sequence of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more contiguous nucleosides.
在一些實施例中,組合物包含抑制目標蛋白之表現的寡核苷酸,其中該寡核苷酸包含含有有義股及反義股的siRNA,其中有義股及反義股形成雙股RNA雙螺旋體。在一些實施例中,雙股RNA雙螺旋體之第一鹼基對為AU鹼基對。In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises an siRNA containing a sense strand and an antisense strand, wherein the sense strand and antisense strand form a double-stranded RNA. Double helix. In some embodiments, the first base pair of the double-stranded RNA duplex is an AU base pair.
在一些實施例中,有義股進一步包含3'懸垂物。在一些實施例中,3'懸垂物包含1、2、3、4、5、6、7、8、9或10個核苷,或由前述數目中之任兩者限定的核苷酸範圍。在一些實施例中,3'懸垂物包含1、2或更多個核苷。在一些實施例中,3'懸垂物包含2個核苷。在一些實施例中,有義股進一步包含5'懸垂物。在一些實施例中,5'懸垂物包含1、2、3、4、5、6、7、8、9或10個核苷,或由前述數目中之任兩者限定的核苷酸範圍。在一些實施例中,5'懸垂物包含1、2或更多個核苷。在一些實施例中,5'懸垂物包含2個核苷。In some embodiments, the prosthetic strand further includes a 3' overhang. In some embodiments, the 3' overhang includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang contains 1, 2, or more nucleosides. In some embodiments, the 3' overhang contains 2 nucleosides. In some embodiments, the sense strand further includes a 5' overhang. In some embodiments, the 5' overhang includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 5' overhang contains 1, 2, or more nucleosides. In some embodiments, the 5' overhang contains 2 nucleosides.
在一些實施例中,反義股進一步包含3'懸垂物。在一些實施例中,3'懸垂物包含1、2、3、4、5、6、7、8、9或10個核苷,或由前述數目中之任兩者限定的核苷酸範圍。在一些實施例中,3'懸垂物包含1、2或更多個核苷。在一些實施例中,3'懸垂物包含2個核苷。在一些實施例中,反義股進一步包含5'懸垂物。在一些實施例中,5'懸垂物包含1、2、3、4、5、6、7、8、9或10個核苷,或由前述數目中之任兩者限定的核苷酸範圍。在一些實施例中,5'懸垂物包含1、2或更多個核苷。在一些實施例中,5'懸垂物包含2個核苷。In some embodiments, the antisense strand further includes a 3' overhang. In some embodiments, the 3' overhang includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 3' overhang contains 1, 2, or more nucleosides. In some embodiments, the 3' overhang contains 2 nucleosides. In some embodiments, the antisense strand further includes a 5' overhang. In some embodiments, the 5' overhang includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleosides, or a range of nucleotides defined by any two of the foregoing numbers. In some embodiments, the 5' overhang contains 1, 2, or more nucleosides. In some embodiments, the 5' overhang contains 2 nucleosides.
在一些實施例中,組合物包含抑制目標蛋白之表現之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股之siRNA,其中siRNA與編碼目標蛋白之人類目標mRNA中之19聚體結合。在一些實施例中,siRNA與人類目標mRNA中之12聚體、13聚體、14聚體、15聚體、16聚體、17聚體、18聚體、19聚體、20聚體、21聚體、22聚體、23聚體、24聚體或25聚體結合。In some embodiments, the composition includes an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide includes an siRNA containing a sense strand and an antisense strand, wherein the siRNA is associated with a human target mRNA encoding the target protein. 19-mer binding. In some embodiments, siRNA and human target mRNA are 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer mer, 22-mer, 23-mer, 24-mer or 25-mer combination.
在一些實施例中,組合物包含抑制目標蛋白之表現之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股之siRNA,其中siRNA與編碼目標蛋白之非人類靈長類動物目標mRNA中的17聚體結合。在一些實施例中,siRNA與非人類靈長類動物目標mRNA中之12聚體、13聚體、14聚體、15聚體、16聚體、17聚體、18聚體、19聚體、20聚體、21聚體、22聚體、23聚體、24聚體或25聚體結合。In some embodiments, the composition includes an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide includes an siRNA containing a sense strand and an antisense strand, wherein the siRNA is associated with a non-human primate encoding the target protein. 17-mer binding in animal target mRNAs. In some embodiments, siRNA is combined with a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer combination.
在一些實施例中,組合物包含抑制目標蛋白之表現之寡核苷酸,其中該寡核苷酸包含含有有義股及反義股之siRNA,其中siRNA與編碼目標蛋白之人類目標mRNA中的19聚體結合。在一些實施例中,siRNA與人類目標mRNA中之12聚體、13聚體、14聚體、15聚體、16聚體、17聚體、及18聚體、19聚體、20聚體、21聚體、22聚體、23聚體、24聚體或25聚體結合。 2. ASO In some embodiments, the composition includes an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide includes an siRNA containing a sense strand and an antisense strand, wherein the siRNA is associated with a human target mRNA encoding the target protein. 19-mer binding. In some embodiments, siRNA and human target mRNA are 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, and 18-mer, 19-mer, 20-mer, 21-mer, 22-mer, 23-mer, 24-mer or 25-mer binding. 2. ASO
在一些實施例中,組合物包含抑制目標寡核苷酸(例如mRNA)之表現之寡核苷酸,其中該寡核苷酸包含反義寡核苷酸(ASO)。在一些實施例中,ASO之長度為12-30個核苷。在一些實施例中,ASO之長度為14-30個核苷。在一些實施例中,ASO之長度為10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷,或由任何兩個前述數目限定的範圍。在一些實施例中,ASO之長度為15-25個核苷。在一些實施例中,ASO之長度為20個核苷。在一些實施例中,ASO包含DNA。In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target oligonucleotide (eg, mRNA), wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the length of the ASO is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleosides, or a range limited by any two of the preceding numbers. In some embodiments, the ASO is 15-25 nucleosides in length. In some embodiments, the ASO is 20 nucleosides in length. In some embodiments, the ASO contains DNA.
在一些實施例中,ASO之長度為12-30個核苷。在一些實施例中,ASO之長度為14-30個核苷。在一些實施例中,ASO之長度為至少約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,ASO之長度為至少12個核苷酸。在一些實施例中,ASO之長度為至少14個核苷酸。在一些實施例中,ASO之長度為至少16個核苷酸。在一些實施例中,ASO之長度為至少18個核苷酸。在一些實施例中,ASO之長度為至少20個核苷酸。在一些實施例中,ASO之長度為至少22個核苷酸。在一些實施例中,ASO之長度為至少24個核苷酸。在一些實施例中,ASO之長度為至少26個核苷酸。在一些實施例中,ASO之長度為至少28個核苷酸。在一些實施例中,ASO之長度為至少30個核苷酸。在一些實施例中,ASO之長度為不超過約10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個核苷。在一些實施例中,ASO之長度為不超過12個核苷酸。在一些實施例中,ASO之長度為不超過14個核苷酸。在一些實施例中,ASO之長度為不超過16個核苷酸。在一些實施例中,ASO之長度為不超過18個核苷酸。在一些實施例中,ASO之長度為不超過20個核苷酸。在一些實施例中,ASO之長度為不超過22個核苷酸。在一些實施例中,ASO之長度為不超過24個核苷酸。在一些實施例中,ASO之長度為不超過26個核苷酸。在一些實施例中,ASO之長度為不超過28個核苷酸。在一些實施例中,ASO之長度為不超過30個核苷酸。In some embodiments, the ASO is 12-30 nucleosides in length. In some embodiments, the ASO is 14-30 nucleosides in length. In some embodiments, the ASO is at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleosides. In some embodiments, the ASO is at least 12 nucleotides in length. In some embodiments, the ASO is at least 14 nucleotides in length. In some embodiments, the ASO is at least 16 nucleotides in length. In some embodiments, the ASO is at least 18 nucleotides in length. In some embodiments, the ASO is at least 20 nucleotides in length. In some embodiments, the ASO is at least 22 nucleotides in length. In some embodiments, the ASO is at least 24 nucleotides in length. In some embodiments, the ASO is at least 26 nucleotides in length. In some embodiments, the ASO is at least 28 nucleotides in length. In some embodiments, the ASO is at least 30 nucleotides in length. In some embodiments, the length of the ASO is no more than about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29 or 30 nucleosides. In some embodiments, the ASO is no more than 12 nucleotides in length. In some embodiments, the ASO is no more than 14 nucleotides in length. In some embodiments, the ASO is no more than 16 nucleotides in length. In some embodiments, the ASO is no more than 18 nucleotides in length. In some embodiments, the ASO is no more than 20 nucleotides in length. In some embodiments, the ASO is no more than 22 nucleotides in length. In some embodiments, the ASO is no more than 24 nucleotides in length. In some embodiments, the ASO is no more than 26 nucleotides in length. In some embodiments, the ASO is no more than 28 nucleotides in length. In some embodiments, the ASO is no more than 30 nucleotides in length.
在一些實施例中,組合物包含抑制目標蛋白之表現之寡核苷酸,其中該寡核苷酸包含長度為約12-30個核苷且包含與編碼目標蛋白之全長人類pre-mRNA目標序列之約12-30個連續核苷互補之核苷序列的ASO;其中(i)該寡核苷酸包含含有經修飾之核苷及/或經修飾之核苷間鍵聯的修飾,及/或(ii)該組合物包含醫藥學上可接受之載劑。In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target protein, wherein the oligonucleotide comprises about 12-30 nucleotides in length and includes a full-length human pre-mRNA target sequence encoding the target protein. An ASO of about 12-30 consecutive nucleoside complementary nucleoside sequences; wherein (i) the oligonucleotide includes a modification containing a modified nucleoside and/or a modified internucleoside linkage, and/or (ii) The composition contains a pharmaceutically acceptable carrier.
在一些實施例中,組合物包含抑制目標蛋白之表現之寡核苷酸,其中該寡核苷酸包含長度為約12-30個核苷且包含與編碼目標蛋白之全長人類目標mRNA序列之約12-30個連續核苷互補之核苷序列的ASO;其中(i)該寡核苷酸包含含有經修飾之核苷及/或經修飾之核苷間鍵聯的修飾,及/或(ii)該組合物包含醫藥學上可接受之載劑。 3. 寡核苷酸修飾模式 In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a protein of interest, wherein the oligonucleotide comprises about 12-30 nucleotides in length and contains about 100% of the full-length human target mRNA sequence encoding the target protein. An ASO of 12-30 consecutive nucleoside complementary nucleoside sequences; wherein (i) the oligonucleotide contains modifications containing modified nucleosides and/or modified internucleoside linkages, and/or (ii) ) The composition includes a pharmaceutically acceptable carrier. 3. Oligonucleotide modification patterns
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含含有經修飾之核苷及/或經修飾之核苷間鍵聯的修飾,及/或(ii)組合物包含醫藥學上可接受之載劑。在一些實施例中,寡核苷酸包含含有經修飾之核苷及/或經修飾之核苷間鍵聯的修飾。在一些實施例中,寡核苷酸包含經修飾之核苷間鍵聯。在一些實施例中,經修飾之核苷間鍵聯包含烷基膦酸酯、硫代磷酸酯、甲基磷酸酯、二硫代磷酸酯、烷基硫代磷酸酯、胺基磷酸酯、胺基甲酸酯、碳酸酯、磷酸三酯、乙醯胺酸酯或羧甲基酯,或其組合。在一些實施例中,經修飾之核苷間鍵聯包含一或多個硫代磷酸酯鍵聯。經修飾之核苷間鍵聯之益處可包括降低之毒性或改良之藥物動力學。In some embodiments, the composition includes an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide includes a modification that includes a modified nucleoside and/or a modified internucleoside linkage, and/ or (ii) the composition contains a pharmaceutically acceptable carrier. In some embodiments, oligonucleotides comprise modifications containing modified nucleosides and/or modified internucleoside linkages. In some embodiments, oligonucleotides comprise modified internucleoside linkages. In some embodiments, the modified internucleoside linkage includes alkylphosphonate, phosphorothioate, methylphosphate, phosphorodithioate, alkylphosphorothioate, aminophosphate, amine formate, carbonate, phosphate triester, acetamidate or carboxymethyl ester, or a combination thereof. In some embodiments, modified internucleoside linkages comprise one or more phosphorothioate linkages. Benefits of modified internucleoside linkages may include reduced toxicity or improved pharmacokinetics.
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含經修飾之核苷間鍵聯,其中寡核苷酸包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個經修飾之核苷間鍵聯,或由前述數目中之任兩者定義的經修飾之核苷間鍵聯範圍。在一些實施例中,寡核苷酸包含不超過18個經修飾之核苷間鍵聯。在一些實施例中,寡核苷酸包含不超過20個經修飾之核苷間鍵聯。在一些實施例中,寡核苷酸包含2個或更多個經修飾之核苷間鍵聯、3個或更多個經修飾之核苷間鍵聯、4個或更多個經修飾之核苷間鍵聯、5個或更多個經修飾之核苷間鍵聯、6個或更多個經修飾之核苷間鍵聯、7個或更多個經修飾之核苷間鍵聯、8個或更多個經修飾之核苷間鍵聯、9個或更多個經修飾之核苷間鍵聯、10個或更多個經修飾之核苷間鍵聯、11個或更多個經修飾之核苷間鍵聯、12個或更多個經修飾之核苷間鍵聯、13個或更多個經修飾之核苷間鍵聯、14個或更多個經修飾之核苷間鍵聯、15個或更多個經修飾之核苷間鍵聯、16個或更多個經修飾之核苷間鍵聯、17個或更多個經修飾之核苷間鍵聯、18個或更多個經修飾之核苷間鍵聯、19個或更多個經修飾之核苷間鍵聯、或20個或更多個經修飾之核苷間鍵聯。In some embodiments, the composition comprises an oligonucleotide bound to a target oligonucleotide, wherein the oligonucleotide comprises a modified internucleoside linkage, wherein the oligonucleotide comprises 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 modified internucleoside linkages, or any two of the foregoing numbers The range of modified internucleoside linkages defined by In some embodiments, the oligonucleotide contains no more than 18 modified internucleoside linkages. In some embodiments, the oligonucleotide contains no more than 20 modified internucleoside linkages. In some embodiments, the oligonucleotide contains 2 or more modified internucleoside linkages, 3 or more modified internucleoside linkages, 4 or more modified internucleoside linkages. Internucleoside linkage, 5 or more modified internucleoside linkages, 6 or more modified internucleoside linkages, 7 or more modified internucleoside linkages , 8 or more modified internucleoside linkages, 9 or more modified internucleoside linkages, 10 or more modified internucleoside linkages, 11 or more Multiple modified internucleoside linkages, 12 or more modified internucleoside linkages, 13 or more modified internucleoside linkages, 14 or more modified internucleoside linkages Internucleoside linkage, 15 or more modified internucleoside linkages, 16 or more modified internucleoside linkages, 17 or more modified internucleoside linkages , 18 or more modified internucleoside linkages, 19 or more modified internucleoside linkages, or 20 or more modified internucleoside linkages.
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含經修飾之核苷。在一些實施例中,經修飾之核苷包含鎖核酸(LNA)、己糖醇核酸(HLA)、環己烯核酸(CeNA)、2'-甲氧基乙基、2'-O-烷基、2'-O-烯丙基、2'-氟或2'-去氧基,或其組合。在一些實施例中,經修飾之核苷包含LNA。在一些實施例中,經修飾之核苷包含2',4'經約束之乙基核酸。在一些實施例中,經修飾之核苷包含HLA。在一些實施例中,經修飾之核苷包含CeNA。在一些實施例中,經修飾之核苷包含2'-甲氧基乙基。在一些實施例中,經修飾之核苷包含2'-O-烷基。在一些實施例中,經修飾之核苷包含2'-O-烯丙基。在一些實施例中,經修飾之核苷包含2'-氟基。在一些實施例中,經修飾之核苷包含2'-去氧基。在一些實施例中,經修飾之核苷包含2'-O-甲基核苷、2'-去氧基氟核苷、2'-O-N-甲基乙醯胺基(2'-O-NMA)核苷、2'-O-二甲基胺基乙氧基乙基(2'-O-DMAEOE)核苷、2'-O-胺丙基(2'-O-AP)核苷或2'-ara-F,或其組合。在一些實施例中,經修飾之核苷包含2'-O-甲基核苷。在一些實施例中,經修飾之核苷包含2'-去氧基氟核苷。在一些實施例中,經修飾之核苷包含2'-O-NMA核苷。在一些實施例中,經修飾之核苷包含2'-O-DMAEOE核苷。在一些實施例中,經修飾之核苷包含2'-O-胺丙基(2'-O-AP)核苷。在一些實施例中,經修飾之核苷包含2'-ara-F。在一些實施例中,經修飾之核苷包含一或多個2'氟基修飾之核苷。在一些實施例中,經修飾之核苷包含2'-O-烷基修飾之核苷。經修飾之核苷之益處可包括降低之毒性或改良之藥物動力學。In some embodiments, the composition comprises an oligonucleotide bound to a target oligonucleotide, wherein the oligonucleotide comprises a modified nucleoside. In some embodiments, modified nucleosides include locked nucleic acid (LNA), hexitol nucleic acid (HLA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-alkyl , 2'-O-allyl, 2'-fluoro or 2'-deoxy, or combinations thereof. In some embodiments, the modified nucleoside comprises LNA. In some embodiments, the modified nucleosides comprise 2',4' constrained ethyl nucleic acids. In some embodiments, the modified nucleoside comprises HLA. In some embodiments, the modified nucleoside includes CeNA. In some embodiments, the modified nucleoside contains 2'-methoxyethyl. In some embodiments, the modified nucleoside contains a 2'-O-alkyl group. In some embodiments, the modified nucleoside contains 2'-O-allyl. In some embodiments, the modified nucleoside contains a 2'-fluoro group. In some embodiments, the modified nucleoside contains a 2'-deoxy group. In some embodiments, the modified nucleoside includes 2'-O-methyl nucleoside, 2'-deoxyfluoronucleoside, 2'-O-N-methylacetamide (2'-O-NMA ) nucleoside, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleoside, 2'-O-aminopropyl (2'-O-AP) nucleoside or 2 '-ara-F, or combinations thereof. In some embodiments, the modified nucleoside comprises a 2'-O-methyl nucleoside. In some embodiments, the modified nucleoside comprises 2'-deoxyfluoronucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-NMA nucleoside. In some embodiments, the modified nucleoside comprises a 2'-O-DMAEOE nucleoside. In some embodiments, the modified nucleoside comprises 2'-O-aminopropyl (2'-O-AP) nucleoside. In some embodiments, the modified nucleoside comprises 2'-ara-F. In some embodiments, the modified nucleosides comprise one or more 2' fluoro modified nucleosides. In some embodiments, the modified nucleosides comprise 2'-O-alkyl modified nucleosides. Benefits of modified nucleosides may include reduced toxicity or improved pharmacokinetics.
在一些實施例中,寡核苷酸包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21個經修飾之核苷,或由前述數目中之任兩者限定的核苷範圍。在一些實施例中,寡核苷酸包含不超過19個經修飾之核苷。在一些實施例中,寡核苷酸包含不超過21個經修飾之核苷。在一些實施例中,寡核苷酸包含2個或更多個經修飾之核苷、3個或更多個經修飾之核苷、4個或更多個經修飾之核苷、5個或更多個經修飾之核苷、6個或更多個經修飾之核苷、7個或更多個經修飾之核苷、8個或更多個經修飾之核苷、9個或更多個經修飾之核苷、10個或更多個經修飾之核苷、11個或更多個經修飾之核苷、12個或更多個經修飾之核苷、13個或更多個經修飾之核苷、14個或更多個經修飾之核苷、15個或更多個經修飾之核苷、16個或更多個經修飾之核苷、17個或更多個經修飾之核苷、18個或更多個經修飾之核苷、19個或更多個經修飾之核苷、20個或更多個經修飾之核苷、或21個或更多個經修飾之核苷。In some embodiments, the oligonucleotides comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 modified nucleosides, or a range of nucleosides defined by either two of the foregoing numbers. In some embodiments, the oligonucleotide contains no more than 19 modified nucleosides. In some embodiments, the oligonucleotide contains no more than 21 modified nucleosides. In some embodiments, the oligonucleotide comprises 2 or more modified nucleosides, 3 or more modified nucleosides, 4 or more modified nucleosides, 5 or More modified nucleosides, 6 or more modified nucleosides, 7 or more modified nucleosides, 8 or more modified nucleosides, 9 or more modified nucleosides, 10 or more modified nucleosides, 11 or more modified nucleosides, 12 or more modified nucleosides, 13 or more modified nucleosides Modified nucleosides, 14 or more modified nucleosides, 15 or more modified nucleosides, 16 or more modified nucleosides, 17 or more modified nucleosides Nucleosides, 18 or more modified nucleosides, 19 or more modified nucleosides, 20 or more modified nucleosides, or 21 or more modified nucleosides glycosides.
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含連接在寡核苷酸之3'或5'端的脂質。在一些實施例中,脂質包含膽固醇、肉豆蔻醯基、軟脂醯基、硬脂醯基、石膽醯基、二十二烷醯基、二十二碳六烯醯基、肉豆蔻基、軟脂基、硬脂基或α-生育酚,或其組合。In some embodiments, the composition comprises an oligonucleotide bound to a target oligonucleotide, wherein the oligonucleotide comprises a lipid attached to the 3' or 5' end of the oligonucleotide. In some embodiments, the lipid includes cholesterol, myristyl, palmityl, stearyl, lithochyl, behenyl, docosahexenyl, myristyl, Palmityl, stearyl or alpha-tocopherol, or combinations thereof.
在一些實施例中,組合物包含抑制目標mRNA之表現的寡核苷酸,其中寡核苷酸包含糖部分。糖部分可包括N-乙醯基半乳糖部分(例如N-乙醯基半乳胺糖(GalNAc)部分)、N-乙醯基葡萄糖部分(例如N-乙醯葡萄糖胺(GlcNAc)部分)、岩藻糖部分或甘露糖部分。糖部分可包括1、2、3或更多個糖分子。糖部分可連接在寡核苷酸之3'或5'端。糖部分可包括N-乙醯基半乳糖部分。糖部分可包括N-乙醯基半乳胺糖(GalNAc)部分。糖部分可包括N-乙醯基葡萄糖部分。糖部分可包括N-乙醯葡萄糖胺(GlcNAc)部分。糖部分可包括岩藻糖部分。糖部分可包括甘露糖部分。N-乙醯基葡萄糖、GlcNAc、岩藻糖或甘露糖可適用於靶向巨噬細胞,此係由於其可靶向或結合甘露糖受體,諸如CD206。In some embodiments, the composition includes an oligonucleotide that inhibits expression of a target mRNA, wherein the oligonucleotide includes a sugar moiety. The sugar moiety may include an N-acetylgalactose moiety (such as an N-acetylgalactamine sugar (GalNAc) moiety), an N-acetylglucose moiety (such as an N-acetylglucosamine (GlcNAc) moiety), Fucose moiety or mannose moiety. The sugar moiety may include 1, 2, 3 or more sugar molecules. The sugar moiety can be attached to the 3' or 5' end of the oligonucleotide. The sugar moiety may include an N-acetylgalactose moiety. The sugar moiety may include an N-acetylgalactamine sugar (GalNAc) moiety. The sugar moiety may include an N-acetylglucose moiety. The sugar moiety may include an N-acetylglucosamine (GlcNAc) moiety. The sugar moiety may include a fucose moiety. The sugar moiety may include a mannose moiety. N-acetylglucose, GlcNAc, fucose or mannose may be suitable for targeting macrophages due to their ability to target or bind to mannose receptors such as CD206.
在一些實施例中,組合物包含抑制目標mRNA之表現之寡核苷酸,其中寡核苷酸包含N-乙醯基半乳胺糖(GalNAc)部分。GalNAc可適用於肝細胞靶向。在一些實施例中,組合物包含GalNAc。在一些實施例中,組合物包含GalNAc衍生物。GalNAc部分可包括1、2、3或更多個GalNAc分子。GalNAc部分可包括二價或三價分支鏈連接子。寡核苷酸可經由二價或三價分支鏈連接子與1、2或3個GalNAc連接。GalNAc部分可連接在寡核苷酸之3'或5'端。In some embodiments, the composition includes an oligonucleotide that inhibits expression of a target mRNA, wherein the oligonucleotide includes an N-acetylgalactamine sugar (GalNAc) moiety. GalNAc may be suitable for hepatocyte targeting. In some embodiments, the composition includes GalNAc. In some embodiments, the composition includes a GalNAc derivative. The GalNAc moiety may include 1, 2, 3 or more GalNAc molecules. The GalNAc moiety may include divalent or trivalent branched chain linkers. Oligonucleotides can be linked to 1, 2 or 3 GalNAc via bivalent or trivalent branched chain linkers. The GalNAc moiety can be attached to the 3' or 5' end of the oligonucleotide.
寡核苷酸可包括嘌呤。嘌呤之實例包括腺嘌呤(A)或鳥嘌呤(G),或其經修飾之型式。寡核苷酸可包括嘧啶。嘧啶之實例包括胞嘧啶(C)、胸腺嘧啶(T)或尿嘧啶(U),或其經修飾之型式。Oligonucleotides may include purines. Examples of purines include adenine (A) or guanine (G), or modified forms thereof. Oligonucleotides may include pyrimidines. Examples of pyrimidines include cytosine (C), thymine (T), or uracil (U), or modified forms thereof.
在一些實施例中,寡核苷酸之嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,寡核苷酸之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,寡核苷酸之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,寡核苷酸之所有嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,寡核苷酸之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,寡核苷酸之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,2'-O-甲基包括2' O-甲基。In some embodiments, the purine of the oligonucleotide comprises a 2' fluoro modified purine. In some embodiments, the purine of the oligonucleotide comprises a 2'-O-methyl modified purine. In some embodiments, the purine of the oligonucleotide includes a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise 2' fluoro modified purines. In some embodiments, all purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, all purines of the oligonucleotide comprise a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, 2'-O-methyl includes 2'O-methyl.
在一些實施例中,寡核苷酸之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,寡核苷酸之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,寡核苷酸之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,寡核苷酸之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,寡核苷酸之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,寡核苷酸之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。In some embodiments, the pyrimidine of the oligonucleotide comprises a 2' fluoro-modified pyrimidine. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the pyrimidine of the oligonucleotide includes a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2' fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines.
在一些實施例中,寡核苷酸之嘌呤包含2'氟基修飾之嘌呤,且寡核苷酸之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,寡核苷酸之嘌呤包含2'-O-甲基修飾之嘌呤,且寡核苷酸之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,寡核苷酸之嘌呤包含2'氟基修飾之嘌呤,且寡核苷酸之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,寡核苷酸之嘌呤包含2'-O-甲基修飾之嘌呤,且寡核苷酸之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,寡核苷酸之嘧啶包含2'氟基修飾之嘧啶,且寡核苷酸之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,寡核苷酸之嘧啶包含2'-O-甲基修飾之嘧啶,且寡核苷酸之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,寡核苷酸之嘧啶包含2'氟基修飾之嘧啶,且寡核苷酸之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,寡核苷酸之嘧啶包含2'-O-甲基修飾之嘧啶,且寡核苷酸之嘌呤包含2'氟基修飾之嘌呤。In some embodiments, the purine of the oligonucleotide comprises a 2' fluoro-modified purine, and the pyrimidine of the oligonucleotide comprises a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the oligonucleotide comprises a 2'-O-methyl modified purine, and the pyrimidine of the oligonucleotide comprises a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the oligonucleotide comprises a 2' fluoro-modified purine, and the pyrimidine of the oligonucleotide comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the purine of the oligonucleotide comprises a 2'-O-methyl modified purine, and the pyrimidine of the oligonucleotide comprises a 2' fluoro-modified pyrimidine. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2' fluoro-modified pyrimidine, and the purine of the oligonucleotide comprises a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-O-methyl modified pyrimidine, and the purine of the oligonucleotide comprises a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2' fluoro-modified pyrimidine, and the purine of the oligonucleotide comprises a 2'-O-methyl modified purine. In some embodiments, the pyrimidine of the oligonucleotide comprises a 2'-O-methyl modified pyrimidine and the purine of the oligonucleotide comprises a 2' fluoro modified purine.
在一些實施例中,寡核苷酸之所有嘌呤包含2'氟基修飾之嘌呤,且寡核苷酸之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,寡核苷酸之所有嘌呤包含2'-O-甲基修飾之嘌呤,且寡核苷酸之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,寡核苷酸之所有嘌呤包含2'氟基修飾之嘌呤,且寡核苷酸之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,寡核苷酸之所有嘌呤包含2'-O-甲基修飾之嘌呤,且寡核苷酸之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,寡核苷酸之所有嘧啶包含2'氟基修飾之嘧啶,且寡核苷酸之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,寡核苷酸之所有嘧啶包含2'-O-甲基修飾之嘧啶,且寡核苷酸之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,寡核苷酸之所有嘧啶包含2'氟基修飾之嘧啶,且寡核苷酸之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,寡核苷酸之所有嘧啶包含2'-O-甲基修飾之嘧啶,且寡核苷酸之所有嘌呤包含2'氟基修飾之嘌呤。 4. siRNA 修飾模式 In some embodiments, all purines of the oligonucleotide comprise 2' fluoro-modified purines, and all pyrimidines of the oligonucleotide comprise a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2'-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise a combination of 2' fluoro and 2'-O-methyl modified pyrimidines. mixture. In some embodiments, all purines of the oligonucleotide comprise 2'fluoro-modified purines, and all pyrimidines of the oligonucleotide comprise 2'-O-methyl-modified pyrimidines. In some embodiments, all purines of the oligonucleotide comprise 2'-O-methyl modified purines, and all pyrimidines of the oligonucleotide comprise 2' fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2' fluoro-modified pyrimidines, and all purines of the oligonucleotide comprise a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise a combination of 2' fluoro and 2'-O-methyl modified purines. mixture. In some embodiments, all pyrimidines of the oligonucleotide comprise 2' fluoro-modified pyrimidines, and all purines of the oligonucleotide comprise 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the oligonucleotide comprise 2'-O-methyl modified pyrimidines, and all purines of the oligonucleotide comprise 2' fluoro-modified purines. 4. siRNA modification pattern
在一些實施例中,有義股包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28或29個經修飾之核苷間鍵聯,或由前述整數中之任兩者限定的經修飾之核苷間鍵聯範圍。在一些實施例中,有義股包含1-11個經修飾之核苷間鍵聯。在一些實施例中,有義股包含2-6個經修飾之核苷間鍵聯。在一些實施例中,有義股包含5個經修飾之核苷間鍵聯。在一些實施例中,有義股包含4個經修飾之核苷間鍵聯。In some embodiments, the right shares include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the foregoing integers. In some embodiments, the sense strand contains 1-11 modified internucleoside linkages. In some embodiments, the sense strand contains 2-6 modified internucleoside linkages. In some embodiments, the sense strand contains 5 modified internucleoside linkages. In some embodiments, the sense strand contains 4 modified internucleoside linkages.
在一些實施例中,反義股包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28或29個經修飾之核苷間鍵聯,或由前述整數中之任兩者限定的經修飾之核苷間鍵聯範圍。在一些實施例中,反義股包含1-11個經修飾之核苷間鍵聯。在一些實施例中,反義股包含2-6個經修飾之核苷間鍵聯。在一些實施例中,反義股包含5個經修飾之核苷間鍵聯。在一些實施例中,反義股包含4個經修飾之核苷間鍵聯。In some embodiments, antisense strands include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 modified internucleoside linkages, or a range of modified internucleoside linkages defined by any two of the foregoing integers. In some embodiments, the antisense strand contains 1-11 modified internucleoside linkages. In some embodiments, the antisense strand contains 2-6 modified internucleoside linkages. In some embodiments, the antisense strand contains 5 modified internucleoside linkages. In some embodiments, the antisense strand contains 4 modified internucleoside linkages.
在一些實施例中,有義股包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個經修飾之核苷,或由前述整數中之任兩者限定的經修飾之核苷範圍。在一些實施例中,有義股包含12-19個經修飾之核苷。在一些實施例中,有義股包含12-21個經修飾之核苷。在一些實施例中,有義股包含19個經修飾之核苷。在一些實施例中,有義股包含21個經修飾之核苷。In some embodiments, the right shares include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 modified nucleosides, or a range of modified nucleosides defined by any two of the foregoing integers. In some embodiments, the sense strand contains 12-19 modified nucleosides. In some embodiments, the sense strand contains 12-21 modified nucleosides. In some embodiments, the sense strand contains 19 modified nucleosides. In some embodiments, the sense strand contains 21 modified nucleosides.
在一些實施例中,反義股包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30個經修飾之核苷,或由前述整數中之任兩者限定的經修飾之核苷範圍。在一些實施例中,反義股包含12-19個經修飾之核苷。在一些實施例中,反義股包含12-21個經修飾之核苷。在一些實施例中,反義股包含19個經修飾之核苷。在一些實施例中,反義股包含21個經修飾之核苷。In some embodiments, antisense strands include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 modified nucleosides, or a range of modified nucleosides defined by any two of the foregoing integers. In some embodiments, the antisense strand contains 12-19 modified nucleosides. In some embodiments, the antisense strand contains 12-21 modified nucleosides. In some embodiments, the antisense strand contains 19 modified nucleosides. In some embodiments, the antisense strand contains 21 modified nucleosides.
在一些實施例中,有義股或反義股進一步包含至少2個與有義股或反義股之3'端連接之額外核苷。在一些實施例中,有義股或反義股包含2個與有義股或反義股之3'端連接之額外核苷。作為有義股之一部分,額外核苷可能與目標mRNA互補或可能不與其互補。反義股之額外核苷可包括尿嘧啶。反義股之2個額外核苷可均包括尿嘧啶。In some embodiments, the sense strand or antisense strand further comprises at least 2 additional nucleosides linked to the 3' end of the sense strand or antisense strand. In some embodiments, the sense or antisense strand contains 2 additional nucleosides linked to the 3' end of the sense or antisense strand. As part of the sense strand, the additional nucleosides may or may not be complementary to the target mRNA. Additional nucleosides of the antisense strand may include uracil. The two additional nucleosides of the antisense strand may both include uracil.
在一些實施例中,有義股或反義股進一步包含至少2個與有義股或反義股之3'端連接之額外核苷。在一些實施例中,有義股或反義股包含2個與有義股或反義股之3'端連接之額外核苷。有義股之額外核苷可包括尿嘧啶。有義股之2個額外核苷可均包括尿嘧啶。In some embodiments, the sense strand or antisense strand further comprises at least 2 additional nucleosides linked to the 3' end of the sense strand or antisense strand. In some embodiments, the sense or antisense strand contains 2 additional nucleosides linked to the 3' end of the sense or antisense strand. Additional nucleosides of the sense strand may include uracil. The two additional nucleosides of the sense strand may both include uracil.
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含含有有義股及反義股之siRNA,其中有義股包含修飾模式。在一些實施例中,有義股包含修飾模式1S:5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式1S#2:5'-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式2S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式2S#2:5'-nnnnNfnNfNfNfnnnnnnnnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式3S:5'-nsnsnnNfnNfnNfnnnnnnnnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式3S#2:5'-nnnnNfnNfnNfnnnnnnnnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,有義股包含修飾模式4S:5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式4S#2:5'-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式5S:5'-nsnsnnNfnNfNfNfnnnnnnnnnnsnsnN-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式5S#2:5'-nnnnNfnNfNfNfnnnnnnnnnnsnsnN-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式6S:5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式6S#2:5'-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,「s」為硫代磷酸酯鍵聯,且N包含一或多個核苷。在一些實施例中,有義股包含修飾模式1S、2S、3S、4S、5S或6S中之任一者。在一些實施例中,有義股包含修飾模式1S#2、2S#2、3S#2、4S#2、5S#2或6S#2中之任一者。在一些實施例中,有義股包含修飾模式1S、3S、4S或6S中之任一者。在一些實施例中,有義股包含修飾模式1S#2、3S#2、4S#2或6S#2中之任一者。修飾模式1S-6S中之任一者可包括與3'端連接之GalNAc配體。修飾模式1S-6S中之任一者可包括與5'端連接之GalNAc配體。修飾模式1S-6S#2中之任一者可包括與3'端連接之GalNAc配體。修飾模式1S-6S#2中之任一者可包括與5'端連接之GalNAc配體。In some embodiments, the compositions comprise oligonucleotides that bind to a target oligonucleotide, wherein the oligonucleotides comprise siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises a modification pattern. In some embodiments, the sense strand includes modification pattern 1S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 1S#2: 5'-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 2S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 2S#2: 5'-nnnnNfnNfNfNfnnnnnnnnnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 3S: 5'-nsnsnnNfnNfnNfnnnnnnnnnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 3S#2: 5'-nnnnNfnNfnNfnnnnnnnnnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside nucleoside, and "s" is a phosphorothioate linkage. In some embodiments, the sense strand includes modification pattern 4S: 5'-NfsnsNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes modification pattern 4S#2: 5'-NfnNfnNfnNfNfNfnNfnNfnNfnNfnNfsnsnN-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside Nucleosides, "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes modification pattern 5S: 5'-nsnsnnNfnNfNfNfnnnnnnnnnnnsnsnN-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes modification pattern 5S#2: 5'-nnnnNfnNfNfNfnnnnnnnnnnnsnsnN-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside Nucleosides, "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes modification pattern 6S: 5'-NfsnsNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes modification pattern 6S#2: 5'-NfnNfnNfnNfnNfnNfnNfnNfnNfnNfsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside Nucleosides, "s" is a phosphorothioate linkage, and N contains one or more nucleosides. In some embodiments, the sense strand includes any of modification patterns 1S, 2S, 3S, 4S, 5S, or 6S. In some embodiments, the sense strand includes any of modification patterns 1S#2, 2S#2, 3S#2, 4S#2, 5S#2, or 6S#2. In some embodiments, the sense strand includes any of modification patterns 1S, 3S, 4S, or 6S. In some embodiments, the sense strand includes any of modification patterns 1S#2, 3S#2, 4S#2, or 6S#2. Any of the modification patterns 1S-6S may include a GalNAc ligand linked to the 3' end. Any of the modification patterns 1S-6S may include a GalNAc ligand linked to the 5' end. Any of the modification patterns 1S-6S#2 may include a GalNAc ligand linked to the 3' end. Any of the modification patterns 1S-6S#2 may include a GalNAc ligand linked to the 5' end.
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含含有有義股及反義股之siRNA,其中反義股包含修飾模式。在一些實施例中,反義股包含修飾模式1AS:5'-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式2AS:5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式3AS:5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式4AS:5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式5AS:5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式6AS:5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式7AS:5'-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式8AS:5'-nsNfsnnnnnnnnnnnNfnnnnnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,反義股包含修飾模式9AS:5'-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3',其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。修飾模式1AS-9AS中之任一者可包括與3'端連接之GalNAc配體。修飾模式1AS-9AS中之任一者可包括與5'端連接之GalNAc配體。In some embodiments, the compositions comprise oligonucleotides that bind to a target oligonucleotide, wherein the oligonucleotides comprise siRNA comprising a sense strand and an antisense strand, wherein the antisense strand comprises a modification pattern. In some embodiments, the antisense strand comprises modification pattern 1AS: 5'-nsNfsnNfnNfnNfnNfnnnNfnNfnNfnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 2AS: 5'-nsNfsnnnNfnNfNfnnnnNfnNfnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 3AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 4AS: 5'-nsNfsnNfnNfnnnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 5AS: 5'-nsNfsnnnNfnNfnnnnnNfnNfnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 6AS: 5'-nsNfsnNfnNfnNfnNfnNfnNfnNfnNfnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 7AS: 5'-nsNfsnNfnNfnNfNfnnnnNfnNfnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 8AS: 5'-nsNfsnnnnnnnnnnnnNfnnnnnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl-modified nucleoside , and "s" is a phosphorothioate linkage. In some embodiments, the antisense strand comprises modification pattern 9AS: 5'-nsNfsnnnNfnnnnnnnNfnNfnNfnsnsn-3', where "Nf" is a 2' fluoro-modified nucleoside and "n" is a 2' O-methyl modified nucleoside , and "s" is a phosphorothioate linkage. Any of the modification patterns 1AS-9AS may include a GalNAc ligand linked to the 3' end. Any of the modification patterns 1AS-9AS may include a GalNAc ligand linked to the 5' end.
修飾模式中之任一者中之修飾可視情況選用。舉例而言,修飾模式1S-6S、1S#2-6S#2或1AS-9AS中之任一者中之1、2、3或更多個硫代磷酸酯鍵聯可經未經修飾之鍵聯或經不同的經修飾之鍵聯置換。在一些情況下,修飾模式1S-6S或1AS-9AS中之任一者中之1、2、3或更多個經修飾之核苷可經未經修飾之核苷或經不同的經修飾之核苷置換。The modifications in any of the modification modes can be selected depending on the situation. For example, 1, 2, 3 or more phosphorothioate linkages in any of the modification patterns 1S-6S, 1S#2-6S#2, or 1AS-9AS may be unmodified linkages The linkage may be replaced by a different modified linkage. In some cases, 1, 2, 3 or more modified nucleosides in any of the modification patterns 1S-6S or 1AS-9AS can be unmodified nucleosides or different modified nucleosides. Nucleoside substitution.
在一些實施例中,組合物包含抑制目標mRNA之表現之寡核苷酸,其中寡核苷酸包含含有有義股及反義股之siRNA,其中有義股包含修飾模式1S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式2S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式4S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式5S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式1S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式2S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式4S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式5S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,反義股包含修飾模式1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。在一些實施例中,有義股或反義股包含修飾模式ASO1。In some embodiments, the composition comprises an oligonucleotide that inhibits the expression of a target mRNA, wherein the oligonucleotide comprises an siRNA comprising a sense strand and an antisense strand, wherein the sense strand comprises modification pattern 1S, and the antisense strand Contains modification modes 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 2S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 3S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 4S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 5S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 6S and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand includes modification pattern 1S#2 and the antisense strand includes modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 2S#2 and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand comprises modification pattern 3S#2 and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the sense strand includes modification pattern 4S#2 and the antisense strand includes modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand includes modification pattern 5S#2 and the antisense strand includes modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense strand comprises modification pattern 6S#2 and the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS or 9AS. In some embodiments, the antisense strand comprises modification pattern 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS. In some embodiments, the sense or antisense strand comprises modification pattern ASO1.
可使用有義及反義修飾模式之任何組合。在一些實施例中,有義股包含修飾模式1S,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式2S,且反義股包含修飾模式2AS。在一些實施例中,有義股包含修飾模式2S,且反義股包含修飾模式3AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式4AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式5AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式6AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式7AS。在一些實施例中,有義股包含修飾模式3S,且反義股包含修飾模式8AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式4AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式5AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式6AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式7AS。在一些實施例中,有義股包含修飾模式6S,且反義股包含修飾模式8AS。在一些實施例中,有義股包含修飾模式1S#2,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式2S#2,且反義股包含修飾模式2AS。在一些實施例中,有義股包含修飾模式2S#2,且反義股包含修飾模式3AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式4AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式5AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式6AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式7AS。在一些實施例中,有義股包含修飾模式3S#2,且反義股包含修飾模式8AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式1AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式4AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式5AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式6AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式7AS。在一些實施例中,有義股包含修飾模式6S#2,且反義股包含修飾模式8AS。Any combination of sense and antisense modification patterns can be used. In some embodiments, the sense strand includes modification pattern 1S and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 2S and the antisense strand includes modification pattern 2AS. In some embodiments, the sense strand includes modification pattern 2S and the antisense strand includes modification pattern 3AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 4AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 5AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 6AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 7AS. In some embodiments, the sense strand includes modification pattern 3S and the antisense strand includes modification pattern 8AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 4AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 5AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 6AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 7AS. In some embodiments, the sense strand includes modification pattern 6S and the antisense strand includes modification pattern 8AS. In some embodiments, the sense strand includes modification pattern 1S#2 and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 2S#2 and the antisense strand includes modification pattern 2AS. In some embodiments, the sense strand includes modification pattern 2S#2 and the antisense strand includes modification pattern 3AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 4AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 5AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 6AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 7AS. In some embodiments, the sense strand includes modification pattern 3S#2 and the antisense strand includes modification pattern 8AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 1AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 4AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 5AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 6AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 7AS. In some embodiments, the sense strand includes modification pattern 6S#2 and the antisense strand includes modification pattern 8AS.
在一些實施例中,有義股之嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,有義股之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,有義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,有義股之所有嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,有義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。In some embodiments, the sense purine comprises a 2' fluoro-modified purine. In some embodiments, the sense purine comprises a 2'-O-methyl modified purine. In some embodiments, the sense purine includes a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise 2' fluoro-modified purines. In some embodiments, all purines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, all purines of the sense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified purines.
在一些實施例中,有義股之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,有義股之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,有義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,有義股之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,有義股之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,有義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。In some embodiments, the sense pyrimidine comprises a 2' fluoro-modified pyrimidine. In some embodiments, the sense pyrimidine comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the sense pyrimidine comprises a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2' fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines.
在一些實施例中,有義股之嘌呤包含2'氟基修飾之嘌呤,且有義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,有義股之嘌呤包含2'-O-甲基修飾之嘌呤,且有義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,有義股之嘌呤包含2'氟基修飾之嘌呤,且有義股之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,有義股之嘌呤包含2'-O-甲基修飾之嘌呤,且有義股之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,有義股之嘧啶包含2'氟基修飾之嘧啶,且有義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,有義股之嘧啶包含2'-O-甲基修飾之嘧啶,且有義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,有義股之嘧啶包含2'氟基修飾之嘧啶,且有義股之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,有義股之嘧啶包含2'-O-甲基修飾之嘧啶,且有義股之嘌呤包含2'氟基修飾之嘌呤。In some embodiments, the purine of the sense strand comprises a 2' fluoro-modified purine, and the pyrimidine of the sense strand comprises a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the sense strand includes a 2'-O-methyl modified purine, and the pyrimidine of the sense strand includes a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the sense strand comprises a 2' fluoro-modified purine, and the pyrimidine of the sense strand comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the purine of the sense strand comprises a 2'-O-methyl modified purine, and the pyrimidine of the sense strand comprises a 2' fluoro-modified pyrimidine. In some embodiments, the pyrimidine of the sense strand comprises a 2' fluoro-modified pyrimidine, and the purine of the sense strand comprises a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the sense strand includes a 2'-O-methyl modified pyrimidine, and the purine of the sense strand includes a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the sense strand comprises a 2' fluoro-modified pyrimidine, and the purine of the sense strand comprises a 2'-O-methyl modified purine. In some embodiments, the pyrimidine of the sense strand comprises a 2'-O-methyl modified pyrimidine, and the purine of the sense strand comprises a 2' fluoro-modified purine.
在一些實施例中,有義股之所有嘌呤包含2'氟基修飾之嘌呤,且有義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤,且有義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,有義股之所有嘌呤包含2'氟基修飾之嘌呤,且有義股之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤,且有義股之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,有義股之所有嘧啶包含2'氟基修飾之嘧啶,且有義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,有義股之所有嘧啶包含2'-O-甲基修飾之嘧啶,且有義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,有義股之所有嘧啶包含2'氟基修飾之嘧啶,且有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,有義股之所有嘧啶包含2'-O-甲基修飾之嘧啶,且有義股之所有嘌呤包含2'氟基修飾之嘌呤。In some embodiments, all purines of the sense strand comprise 2' fluoro-modified purines, and all pyrimidines of the sense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines of the sense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2' fluoro-modified purines, and all pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines of the sense strand comprise 2' fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the sense strand comprise 2' fluoro-modified pyrimidines, and all purines of the sense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines, and all purines of the sense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2' fluoro-modified pyrimidines, and all purines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl modified pyrimidines, and all purines of the sense strand comprise 2' fluoro-modified purines.
在一些實施例中,反義股之嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,反義股之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,反義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,反義股之所有嘌呤包含2'氟基修飾之嘌呤。在一些實施例中,反義股之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,反義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。In some embodiments, the antisense purine comprises a 2' fluoro-modified purine. In some embodiments, the antisense purine comprises a 2'-O-methyl modified purine. In some embodiments, the purine of the antisense strand includes a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise 2' fluoro-modified purines. In some embodiments, all purines of the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all purines of the antisense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified purines.
在一些實施例中,反義股之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,反義股之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,反義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,反義股之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,反義股之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,反義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。In some embodiments, the pyrimidine of the antisense strand comprises a 2' fluoro-modified pyrimidine. In some embodiments, the pyrimidine of the antisense strand comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the pyrimidine of the antisense strand includes a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2' fluoro-modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines.
在一些實施例中,反義股之嘌呤包含2'氟基修飾之嘌呤,且反義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,反義股之嘌呤包含2'-O-甲基修飾之嘌呤,且反義股之嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,反義股之嘌呤包含2'氟基修飾之嘌呤,且反義股之嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,反義股之嘌呤包含2'-O-甲基修飾之嘌呤,且反義股之嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,反義股之嘧啶包含2'氟基修飾之嘧啶,且反義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,反義股之嘧啶包含2'-O-甲基修飾之嘧啶,且反義股之嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,反義股之嘧啶包含2'氟基修飾之嘧啶,且反義股之嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,反義股之嘧啶包含2'-O-甲基修飾之嘧啶,且反義股之嘌呤包含2'氟基修飾之嘌呤。In some embodiments, the purine of the antisense strand comprises a 2' fluoro-modified purine, and the pyrimidine of the antisense strand comprises a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the antisense strand comprises a 2'-O-methyl modified purine, and the pyrimidine of the antisense strand comprises a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, the purine of the antisense strand comprises a 2' fluoro-modified purine and the pyrimidine of the antisense strand comprises a 2'-O-methyl modified pyrimidine. In some embodiments, the purine of the antisense strand comprises a 2'-O-methyl modified purine and the pyrimidine of the antisense strand comprises a 2' fluoro modified pyrimidine. In some embodiments, the pyrimidine of the antisense strand comprises a 2' fluoro-modified pyrimidine, and the purine of the antisense strand comprises a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the antisense strand comprises a 2'-O-methyl modified pyrimidine, and the purine of the antisense strand comprises a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, the pyrimidine of the antisense strand comprises a 2' fluoro-modified pyrimidine, and the purine of the antisense strand comprises a 2'-O-methyl modified purine. In some embodiments, the pyrimidine of the antisense strand comprises a 2'-O-methyl modified pyrimidine and the purine of the antisense strand comprises a 2' fluoro modified purine.
在一些實施例中,反義股之所有嘌呤包含2'氟基修飾之嘌呤,且反義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,反義股之所有嘌呤包含2'-O-甲基修飾之嘌呤,且反義股之所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶之混合物。在一些實施例中,反義股之所有嘌呤包含2'氟基修飾之嘌呤,且反義股之所有嘧啶包含2'-O-甲基修飾之嘧啶。在一些實施例中,反義股之所有嘌呤包含2'-O-甲基修飾之嘌呤,且反義股之所有嘧啶包含2'氟基修飾之嘧啶。在一些實施例中,反義股之所有嘧啶包含2'氟基修飾之嘧啶,且反義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,反義股之所有嘧啶包含2'-O-甲基修飾之嘧啶,且反義股之所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤之混合物。在一些實施例中,反義股之所有嘧啶包含2'氟基修飾之嘧啶,且反義股之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,反義股之所有嘧啶包含2'-O-甲基修飾之嘧啶,且反義股之所有嘌呤包含2'氟基修飾之嘌呤。In some embodiments, all purines of the antisense strand comprise 2' fluoro-modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2'-O-methyl modified purines, and all pyrimidines of the antisense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2' fluoro-modified purines, and all pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines. In some embodiments, all purines of the antisense strand comprise 2'-O-methyl modified purines and all pyrimidines of the antisense strand comprise 2' fluoro modified pyrimidines. In some embodiments, all pyrimidines of the antisense strand comprise 2' fluoro-modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2' fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines, and all purines of the antisense strand comprise a mixture of 2'fluoro and 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2' fluoro-modified pyrimidines, and all purines of the antisense strand comprise 2'-O-methyl modified purines. In some embodiments, all pyrimidines of the antisense strand comprise 2'-O-methyl modified pyrimidines and all purines of the antisense strand comprise 2' fluoro modified purines.
在一些情況下,寡核苷酸包含特定修飾模式。在一些實施例中,自寡核苷酸之一股之5'端計數之位置9可具有2'F修飾。在一些實施例中,當寡核苷酸之一股之位置9為嘧啶時,則寡核苷酸之一股中之所有嘌呤均具有2'OMe修飾。在一些實施例中,當位置9為有義股之位置5與11之間的唯一嘧啶時,則位置9為寡核苷酸之一股中具有2'F修飾的唯一位置。在一些實施例中,當位置9及寡核苷酸之一股之位置5與11之間的唯一一個其他鹼基為嘧啶時,則此等嘧啶兩者為寡核苷酸之股中具有2'F修飾的僅有的兩個位置。在一些實施例中,當位置9及寡核苷酸之一股之位置5與11之間的僅有的兩個其他鹼基為嘧啶,且彼等兩個其他嘧啶處於相鄰位置以使得將不存在三個連續的2'F修飾時,則可進行2'F修飾之任何組合,得到總共三個2'F修飾。在一些實施例中,當寡核苷酸之一股之位置5與11之間存在超過2個嘧啶時,則允許具有2'F修飾之嘧啶的所有組合總共具有三至五個2'F修飾,其限制條件為寡核苷酸之股不具有三個連續的2'F修飾。在一些情況下,siRNA中之任一者之寡核苷酸之一股包含符合寡核苷酸之任何或所有此等股規則的修飾模式。In some cases, oligonucleotides contain specific modification patterns. In some embodiments, position 9, counted from the 5' end of one strand of the oligonucleotide, can have a 2'F modification. In some embodiments, when position 9 of one strand of the oligonucleotide is a pyrimidine, then all purines in one strand of the oligonucleotide have a 2'OMe modification. In some embodiments, when position 9 is the only pyrimidine between positions 5 and 11 of the sense strand, then position 9 is the only position in one strand of the oligonucleotide with a 2'F modification. In some embodiments, when position 9 and the only other base between positions 5 and 11 of one strand of the oligonucleotide are pyrimidines, then both of these pyrimidines are 2 in the strand of the oligonucleotide. The only two positions modified by 'F. In some embodiments, when the only two other bases between position 9 and positions 5 and 11 of one strand of the oligonucleotide are pyrimidines, and those two other pyrimidines are in adjacent positions such that When there are not three consecutive 2'F modifications, any combination of 2'F modifications can be performed, resulting in a total of three 2'F modifications. In some embodiments, when more than 2 pyrimidines are present between positions 5 and 11 on one strand of an oligonucleotide, then all combinations of pyrimidines with 2'F modifications are allowed to have a total of three to five 2'F modifications , with the restriction that the oligonucleotide strand does not have three consecutive 2'F modifications. In some cases, one strand of the oligonucleotide of any of the siRNAs contains a modification pattern that conforms to any or all of the rules for such strands of the oligonucleotide.
在一些實施例中,當寡核苷酸之一股之位置9為嘌呤時,則寡核苷酸之一股中之所有嘌呤均具有2'OMe修飾。在一些實施例中,當位置9為有義股之位置5與11之間的唯一嘌呤時,則位置9為寡核苷酸之一股中具有2'F修飾的唯一位置。在一些實施例中,當位置9及寡核苷酸之一股之位置5與11之間的唯一一個其他鹼基為嘌呤時,則此等嘌呤兩者為寡核苷酸之一股中具有2'F修飾的僅有的兩個位置。在一些實施例中,當位置9及寡核苷酸之一股之位置5與11之間的僅有的兩個其他鹼基為嘌呤,且彼等兩個其他嘌呤處於相鄰位置以使得將不存在三個連續的2'F修飾時,則可進行2'F修飾之任何組合,得到總共三個2'F修飾。在一些實施例中,當寡核苷酸之一股之位置5與11之間存在超過2個嘌呤時,則允許具有2'F修飾之嘌呤之所有組合總共具有三至五個2'F修飾,其限制條件為寡核苷酸之一股不具有三個連續的2'F修飾。在一些情況下,siRNA中之任一者之寡核苷酸之一股包含符合寡核苷酸之任何或所有此等股規則的修飾模式。In some embodiments, when position 9 of one strand of the oligonucleotide is a purine, then all purines in one strand of the oligonucleotide have a 2'OMe modification. In some embodiments, when position 9 is the only purine between positions 5 and 11 of the sense strand, then position 9 is the only position in one strand of the oligonucleotide with a 2'F modification. In some embodiments, when the only other base between position 9 and positions 5 and 11 of one strand of the oligonucleotide is a purine, then both of these purines are present in one strand of the oligonucleotide. The only two positions modified by 2'F. In some embodiments, when the only two other bases between position 9 and positions 5 and 11 of one strand of the oligonucleotide are purines, and those two other purines are in adjacent positions such that When there are not three consecutive 2'F modifications, any combination of 2'F modifications can be performed, resulting in a total of three 2'F modifications. In some embodiments, when more than 2 purines are present between positions 5 and 11 on one strand of an oligonucleotide, then all combinations of purines with 2'F modifications are allowed to have a total of three to five 2'F modifications , the restriction is that one strand of the oligonucleotide does not have three consecutive 2'F modifications. In some cases, one strand of the oligonucleotide of any of the siRNAs contains a modification pattern that conforms to any or all of the rules for such strands of the oligonucleotide.
在一些情況下,寡核苷酸之一股之位置9可為2'去氧基。在此等情況下,2'F及2'OMe修飾可存在於寡核苷酸之一股之其他位置處。在一些情況下,siRNA中之任一者之寡核苷酸之一股包含符合寡核苷酸之此等股規則的修飾模式。In some cases, position 9 of one strand of the oligonucleotide may be a 2' deoxy group. In such cases, the 2'F and 2'OMe modifications may be present at other positions on one strand of the oligonucleotide. In some cases, one strand of the oligonucleotide of any of the siRNAs contains a modification pattern that conforms to the rules for such strands of oligonucleotides.
在一些實施例中,有義股之位置九包含2'氟基修飾之嘧啶。在一些實施例中,有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤。在一些實施例中,位置5與11之間的1、2、3、4或5個嘧啶包含2'氟基修飾之嘧啶,其限制條件為不存在三個連續的2'氟基修飾之嘧啶。在一些實施例中,反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基經修飾之核苷酸、2'-O-甲基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置九包含2'氟基修飾之嘧啶;有義股之所有嘌呤包含2'-O-甲基修飾之嘌呤;位置5與11之間的1、2、3、4或5個嘧啶包含2'氟基修飾之嘧啶,其限制條件為不存在三個連續的2'氟基修飾之嘧啶;反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸;且反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。In some embodiments, position nine of the sense strand contains a 2' fluoro-modified pyrimidine. In some embodiments, all purines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, 1, 2, 3, 4 or 5 pyrimidines between positions 5 and 11 comprise 2' fluoro-modified pyrimidines, with the proviso that there are no three consecutive 2' fluoro-modified pyrimidines . In some embodiments, the antisense strands comprise 2'-O-methyl modified nucleotides at odd-numbered positions. In some embodiments, the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides, 2'-O-methyl modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand includes a 2' fluoro-modified pyrimidine; all purines of the sense strand include 2'-O-methyl modified purines; positions 1, 2, and 3, 4 or 5 pyrimidines contain 2' fluoro-modified pyrimidines, with the restriction that there are not three consecutive 2' fluoro-modified pyrimidines; the odd-numbered positions of the antisense strand contain 2'-O-methyl modifications nucleotides; and the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides.
在一些實施例中,有義股之位置九包含2'氟基修飾之嘌呤。在一些實施例中,有義股之所有嘧啶包含2'-O-甲基修飾之嘌呤。在一些實施例中,位置5與11之間的1、2、3、4或5個嘌呤包含2'氟基修飾之嘌呤,其限制條件為不存在三個連續的2'氟基修飾之嘌呤。在一些實施例中,反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基經修飾之核苷酸、2'-O-甲基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置九包含2'氟基修飾之嘌呤;有義股之所有嘧啶包含2'-O-甲基修飾之嘧啶;位置5與11之間的1、2、3、4或5個嘌呤包含2'氟基修飾之嘌呤,其限制條件為不存在三個連續的2'氟基修飾之嘌呤;反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸;且反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,不存在三個連續的2'氟基修飾之嘌呤。在一些實施例中,不存在三個連續的2'氟基修飾之嘧啶。In some embodiments, position nine of the sense strand contains a 2' fluoro-modified purine. In some embodiments, all pyrimidines of the sense strand comprise 2'-O-methyl modified purines. In some embodiments, 1, 2, 3, 4 or 5 purines between positions 5 and 11 comprise 2' fluoro-modified purines, with the proviso that there are not three consecutive 2' fluoro-modified purines . In some embodiments, the antisense strands comprise 2'-O-methyl modified nucleotides at odd-numbered positions. In some embodiments, the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides, 2'-O-methyl modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand includes a 2' fluoro-modified purine; all pyrimidines of the sense strand include 2'-O-methyl-modified pyrimidines; positions 1, 2, and 2 between positions 5 and 11 3, 4 or 5 purines contain 2' fluoro-modified purines, with the restriction that there are no three consecutive 2' fluoro-modified purines; the odd-numbered positions of the antisense strand contain 2'-O-methyl modifications nucleotides; and the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, three consecutive 2' fluoro-modified purines are absent. In some embodiments, three consecutive 2' fluoro-modified pyrimidines are absent.
在一些實施例中,有義股之位置九包含未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置5、7及8包含2'氟基修飾之核苷酸。在一些實施例中,有義股之位置10至21中之所有嘧啶包含2'-O-甲基修飾之嘧啶,且位置10至21中之所有嘌呤包含2'-O-甲基修飾之嘌呤或2'氟基修飾之嘌呤。在一些實施例中,反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基經修飾之核苷酸、2'-O-甲基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置九包含未經修飾之去氧核糖核苷酸;有義股之位置5、7及8包含2'氟基修飾之核苷酸;有義股之位置10至21中之所有嘧啶包含2'-O-甲基修飾之嘧啶,且位置10至21中之所有嘌呤包含2'-O-甲基修飾之嘌呤或2'氟基修飾之嘌呤;反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸;且反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。In some embodiments, position nine of the sense strand comprises unmodified deoxyribonucleotides. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2' fluoro-modified nucleotides. In some embodiments, all pyrimidines in positions 10 to 21 of the sense strand comprise 2'-O-methyl modified pyrimidines, and all purines in positions 10 to 21 comprise 2'-O-methyl modified purines Or 2' fluoro modified purine. In some embodiments, the antisense strands comprise 2'-O-methyl modified nucleotides at odd-numbered positions. In some embodiments, the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides, 2'-O-methyl modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand includes unmodified deoxyribonucleotides; positions 5, 7, and 8 of the sense strand include 2' fluoro-modified nucleotides; positions of the sense strand All pyrimidines in positions 10 to 21 contain 2'-O-methyl modified pyrimidines, and all purines in positions 10 to 21 contain 2'-O-methyl modified purines or 2' fluoro modified purines; antisense The odd-numbered positions of the strand contain 2'-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand contain 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides.
在一些實施例中,有義股之位置九包含未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置5、7及8包含2'氟基修飾之核苷酸。在一些實施例中,有義股之位置10至21中之所有嘌呤包含2'-O-甲基修飾之嘌呤,且位置10至21中之所有嘧啶包含2'-O-甲基修飾之嘧啶或2'氟基修飾之嘧啶。在一些實施例中,反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,反義股之偶數編號位置包含2'氟基經修飾之核苷酸、2'-O-甲基修飾之核苷酸及未經修飾之去氧核糖核苷酸。在一些實施例中,有義股之位置九包含未經修飾之去氧核糖核苷酸;有義股之位置5、7及8包含2'氟基修飾之核苷酸;有義股之位置10至21中之所有嘌呤包含2'-O-甲基修飾之嘌呤,且位置10至21中之所有嘧啶包含2'-O-甲基修飾之嘧啶或2'氟基修飾之嘧啶;反義股之奇數編號位置包含2'-O-甲基修飾之核苷酸;且反義股之偶數編號位置包含2'氟基修飾之核苷酸及未經修飾之去氧核糖核苷酸。 5. ASO 修飾模式 In some embodiments, position nine of the sense strand comprises unmodified deoxyribonucleotides. In some embodiments, positions 5, 7, and 8 of the sense strand comprise 2' fluoro-modified nucleotides. In some embodiments, all purines in positions 10 to 21 of the sense strand comprise 2'-O-methyl modified purines, and all pyrimidines in positions 10 to 21 comprise 2'-O-methyl modified pyrimidines Or 2'fluoro-modified pyrimidine. In some embodiments, the antisense strands comprise 2'-O-methyl modified nucleotides at odd-numbered positions. In some embodiments, the even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. In some embodiments, even-numbered positions of the antisense strand include 2' fluoro-modified nucleotides, 2'-O-methyl modified nucleotides, and unmodified deoxyribonucleotides. In some embodiments, position nine of the sense strand includes unmodified deoxyribonucleotides; positions 5, 7, and 8 of the sense strand include 2' fluoro-modified nucleotides; positions of the sense strand All purines in positions 10 to 21 include 2'-O-methyl modified purines, and all pyrimidines in positions 10 to 21 include 2'-O-methyl modified pyrimidines or 2' fluoro modified pyrimidines; antisense The odd-numbered positions of the strand contain 2'-O-methyl modified nucleotides; and the even-numbered positions of the antisense strand contain 2' fluoro-modified nucleotides and unmodified deoxyribonucleotides. 5. ASO modification mode
在一些實施例中,組合物包含與目標寡核苷酸結合之寡核苷酸,其中寡核苷酸包含反義寡核苷酸(ASO)。在一些實施例中,ASO包含修飾模式ASO1:5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsnsn-3',其中「dN」為任何去氧核苷酸,「n」為2'O-甲基或2'O-甲氧基乙基修飾之核苷,且「s」為硫代磷酸酯鍵聯。在一些實施例中,ASO包含修飾模式1S、2S、3S、4S、5S、6S、1AS、2AS、3AS、4AS、5AS、6AS、7AS、8AS或9AS。In some embodiments, the composition comprises an oligonucleotide that binds to a target oligonucleotide, wherein the oligonucleotide comprises an antisense oligonucleotide (ASO). In some embodiments, the ASO includes the modification pattern ASO1: 5'-nsnsnsnsnsdNsdNsdNsdNsdNsdNsdNsdNsdNsdNsnsnsnsn-3', where "dN" is any deoxynucleotide and "n" is 2'O-methyl or 2'O-methoxy Ethyl-modified nucleosides, and "s" is a phosphorothioate linkage. In some embodiments, the ASO includes modification patterns 1S, 2S, 3S, 4S, 5S, 6S, 1AS, 2AS, 3AS, 4AS, 5AS, 6AS, 7AS, 8AS, or 9AS.
在一些實施例中,ASO與GalNAc部分結合。GalNAc部分可與ASO在5'端或3'端結合。在一些實施例中,GalNAc部分與ASO之5'端結合。在一些實施例中,GalNAc部分與ASO之3'端結合。 C. 調配物In some embodiments, the ASO binds to the GalNAc moiety. The GalNAc moiety can bind to the ASO at either the 5' or 3' end. In some embodiments, the GalNAc moiety binds to the 5' end of the ASO. In some embodiments, the GalNAc moiety binds to the 3' end of the ASO. C. Preparations
在一些實施例中,組合物為醫藥組合物。在一些實施例中,組合物為無菌的。在一些實施例中,組合物進一步包含醫藥學上可接受之載劑。調配物可包括化合物(諸如GalNAc部分)及本文所描述之與GalNAc部分結合之寡核苷酸。In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. The formulation may include a compound (such as a GalNAc moiety) and an oligonucleotide described herein that binds to a GalNAc moiety.
在一些實施例中,醫藥學上可接受之載劑包含水。在一些實施例中,醫藥學上可接受之載劑包含緩衝液。在一些實施例中,醫藥學上可接受之載劑包含鹽水溶液。在一些實施例中,醫藥學上可接受之載劑包含水、緩衝液或鹽水溶液。在一些實施例中,組合物包含脂質體。在一些實施例中,醫藥學上可接受之載劑包含脂質體、脂質、奈米粒子、蛋白質、蛋白質-抗體複合物、肽、纖維素、奈米凝膠或其組合。 II. 方法及用途 In some embodiments, the pharmaceutically acceptable carrier includes water. In some embodiments, the pharmaceutically acceptable carrier includes a buffer. In some embodiments, the pharmaceutically acceptable carrier includes a saline solution. In some embodiments, a pharmaceutically acceptable carrier includes water, buffer, or saline solution. In some embodiments, the composition includes liposomes. In some embodiments, pharmaceutically acceptable carriers include liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogels, or combinations thereof. II.Methods and uses
在一些實施例中,本文揭示向個體投與本文所描述之組合物之方法。一些實施例係關於使用本文所描述之組合物,諸如向個體投與組合物。In some embodiments, disclosed herein are methods of administering a composition described herein to an individual. Some embodiments relate to using the compositions described herein, such as administering the composition to an individual.
一些實施例係關於一種治療有需要個體之病症的方法。一些實施例係關於本文所描述之組合物在治療方法中之用途。一些實施例包括向患有病症之個體投與本文所描述之組合物。在一些實施例中,該投與治療個體之病症。在一些實施例中,該組合物治療個體之病症。Some embodiments relate to a method of treating a condition in an individual in need thereof. Some embodiments relate to the use of compositions described herein in methods of treatment. Some embodiments include administering a composition described herein to an individual suffering from a disorder. In some embodiments, the administration treats a condition in the individual. In some embodiments, the composition treats a condition in an individual.
在一些實施例中,治療包含預防、抑制或逆轉個體之病症。一些實施例係關於本文所描述之組合物在預防、抑制或逆轉病症之方法中的用途。一些實施例係關於一種預防、抑制或逆轉有需要之個體之病症的方法。一些實施例包括向患有病症之個體投與本文所描述之組合物。在一些實施例中,該投與預防、抑制或逆轉個體之病症。在一些實施例中,該組合物預防、抑制或逆轉個體之病症。In some embodiments, treatment includes preventing, inhibiting, or reversing a disorder in an individual. Some embodiments relate to the use of compositions described herein in methods of preventing, inhibiting, or reversing disorders. Some embodiments relate to a method of preventing, inhibiting or reversing a disorder in an individual in need thereof. Some embodiments include administering a composition described herein to an individual suffering from a disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the individual. In some embodiments, the composition prevents, inhibits, or reverses a disorder in an individual.
一些實施例係關於一種預防有需要個體之病症的方法。一些實施例係關於本文所描述之組合物在預防病症之方法中的用途。一些實施例包括向患有病症之個體投與本文所描述之組合物。在一些實施例中,該投與預防個體之病症。在一些實施例中,該組合物預防個體之病症。Some embodiments relate to a method of preventing a disorder in an individual in need thereof. Some embodiments relate to the use of compositions described herein in methods of preventing disorders. Some embodiments include administering a composition described herein to an individual suffering from a disorder. In some embodiments, the administration prevents the disorder in the individual. In some embodiments, the composition prevents a disorder in an individual.
一些實施例係關於一種抑制有需要個體之病症的方法。一些實施例係關於本文所描述之組合物在抑制病症之方法中的用途。一些實施例包括向患有病症之個體投與本文所描述之組合物。在一些實施例中,該投與抑制個體之病症。在一些實施例中,該組合物抑制個體之病症。Some embodiments relate to a method of inhibiting a disorder in an individual in need thereof. Some embodiments relate to the use of compositions described herein in methods of inhibiting a disorder. Some embodiments include administering a composition described herein to an individual suffering from a disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.
一些實施例係關於一種逆轉有需要個體之病症的方法。一些實施例係關於本文所描述之組合物在逆轉病症之方法中的用途。一些實施例包括向患有病症之個體投與本文所描述之組合物。在一些實施例中,該投與逆轉個體之病症。在一些實施例中,該組合物逆轉個體之病症。 A. 病症Some embodiments relate to a method of reversing a disorder in an individual in need thereof. Some embodiments relate to the use of compositions described herein in methods of reversing a disorder. Some embodiments include administering a composition described herein to an individual suffering from a disorder. In some embodiments, the administration reverses the disorder in the individual. In some embodiments, the composition reverses the disorder in the individual. A. Disease
本文所描述之方法之一些實施例包括治療有需要個體之病症。在一些實施例中,病症為肝病。肝病之非限制性實例包括肝炎、肝癌、肝纖維化、膽汁鬱積、膽囊疾病、膽道樹疾病、酒精性肝病、非酒精性脂肪性肝炎、肝感染或遺傳性肝病。在一些實施例中,肝病包含肝炎。在一些實施例中,肝病包含肝癌。在一些實施例中,肝病包含肝纖維化。在一些實施例中,肝病包含膽汁鬱積。在一些實施例中,肝病包含膽囊疾病。在一些實施例中,肝病包含膽道樹疾病。在一些實施例中,肝病包含酒精性肝病。在一些實施例中,肝病包含非酒精性脂肪性肝炎。Some embodiments of the methods described herein include treating a condition in an individual in need thereof. In some embodiments, the condition is liver disease. Non-limiting examples of liver diseases include hepatitis, liver cancer, liver fibrosis, cholestasis, gallbladder disease, biliary tree disease, alcoholic liver disease, non-alcoholic steatohepatitis, liver infection, or inherited liver disease. In some embodiments, the liver disease includes hepatitis. In some embodiments, the liver disease includes liver cancer. In some embodiments, the liver disease includes liver fibrosis. In some embodiments, the liver disease includes cholestasis. In some embodiments, liver disease includes gallbladder disease. In some embodiments, the liver disease includes biliary tree disease. In some embodiments, the liver disease includes alcoholic liver disease. In some embodiments, the liver disease includes non-alcoholic steatohepatitis.
在一些實施例中,肝病包含肝感染。在一些實施例中,肝感染包含A型肝炎。在一些實施例中,肝感染包含B型肝炎。在一些實施例中,肝感染包含C型肝炎。In some embodiments, the liver disease includes liver infection. In some embodiments, the liver infection comprises hepatitis A. In some embodiments, the liver infection comprises hepatitis B. In some embodiments, the liver infection comprises hepatitis C.
在一些實施例中,肝病包含遺傳性肝病。在一些實施例中,遺傳性肝病包含血色素沉著症。在一些實施例中,遺傳性肝病包含威爾遜氏病(Wilson disease)。 B. 個體In some embodiments, the liver disease includes a genetic liver disease. In some embodiments, the genetic liver disease includes hemochromatosis. In some embodiments, the inherited liver disease includes Wilson disease. B. Individual
本文所描述之方法之一些實施例包括個體之治療。個體之非限制性實例包括脊椎動物、動物、哺乳動物、狗、貓、牛、嚙齒動物、小鼠、大鼠、靈長類動物、猴及人類。在一些實施例中,個體為脊椎動物。在一些實施例中,個體為動物。在一些實施例中,個體為哺乳動物。在一些實施例中,個體為狗。在一些實施例中,個體為貓。在一些實施例中,個體為牛。在一些實施例中,個體為小鼠。在一些實施例中,個體為大鼠。在一些實施例中,個體為靈長類動物。在一些實施例中,個體為猴。在一些實施例中,個體為動物、哺乳動物、狗、貓、牛、嚙齒動物、小鼠、大鼠、靈長類動物或猴。在一些實施例中,個體為人類。Some embodiments of the methods described herein include treatment of individuals. Non-limiting examples of individuals include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the individual is a vertebrate animal. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the individual is a dog. In some embodiments, the individual is a cat. In some embodiments, the individual is a cow. In some embodiments, the individual is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the individual is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cow, rodent, mouse, rat, primate, or monkey. In some embodiments, the individual is a human.
在一些實施例中,個體為雄性。在一些實施例中,個體為雌性。In some embodiments, the individual is male. In some embodiments, the individual is female.
在一些實施例中,個體之身體質量指數(body mass index;BMI)為25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50或更高,或由前述整數中之任兩者限定的範圍。在一些實施例中,個體超重。在一些實施例中,個體之BMI為25或更高。在一些實施例中,個體之BMI為25-29。在一些實施例中,個體為肥胖的。在一些實施例中,個體之BMI為30或更高。在一些實施例中,個體之BMI為30-39。在一些實施例中,個體之BMI為40-50。在一些實施例中,個體之BMI為25-50。In some embodiments, the individual has a body mass index (BMI) of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or higher, or a range limited by any two of the aforementioned integers. In some embodiments, the individual is overweight. In some embodiments, the individual has a BMI of 25 or higher. In some embodiments, the individual has a BMI of 25-29. In some embodiments, the subject is obese. In some embodiments, the individual has a BMI of 30 or higher. In some embodiments, the individual has a BMI of 30-39. In some embodiments, the individual has a BMI of 40-50. In some embodiments, the individual has a BMI of 25-50.
在一些實施例中,個體≥ 90歲。在一些實施例中,個體≥ 85歲。在一些實施例中,個體≥ 80歲。在一些實施例中,個體≥ 70歲。在一些實施例中,個體≥ 60歲。在一些實施例中,個體≥ 50歲。在一些實施例中,個體≥ 40歲。在一些實施例中,個體≥ 30歲。在一些實施例中,個體≥ 20歲。在一些實施例中,個體≥ 10歲。在一些實施例中,個體≥ 1歲。在一些實施例中,個體≥ 0歲。In some embodiments, the individual is ≥ 90 years old. In some embodiments, the individual is ≥85 years old. In some embodiments, the individual is ≥80 years old. In some embodiments, the individual is ≥70 years old. In some embodiments, the individual is ≥ 60 years old. In some embodiments, the individual is ≥ 50 years old. In some embodiments, the subject is ≥ 40 years old. In some embodiments, the subject is ≥ 30 years old. In some embodiments, the individual is ≥ 20 years old. In some embodiments, the individual is ≥10 years old. In some embodiments, the subject is ≥ 1 year old. In some embodiments, the individual is ≥ 0 years old.
在一些實施例中,個體≤ 100歲。在一些實施例中,個體≤ 90歲。在一些實施例中,個體≤ 85歲。在一些實施例中,個體≤ 80歲。在一些實施例中,個體≤ 70歲。在一些實施例中,個體≤ 60歲。在一些實施例中,個體≤ 50歲。在一些實施例中,個體≤ 40歲。在一些實施例中,個體≤ 30歲。在一些實施例中,個體≤ 20歲。在一些實施例中,個體≤ 10歲。在一些實施例中,個體≤ 1歲。In some embodiments, the individual is ≤ 100 years old. In some embodiments, the individual is ≤ 90 years old. In some embodiments, the individual is ≤ 85 years old. In some embodiments, the individual is ≤ 80 years old. In some embodiments, the individual is ≤ 70 years old. In some embodiments, the individual is ≤ 60 years old. In some embodiments, the individual is ≤ 50 years old. In some embodiments, the individual is ≤ 40 years old. In some embodiments, the individual is ≤ 30 years old. In some embodiments, the individual is ≤ 20 years old. In some embodiments, the individual is ≤ 10 years old. In some embodiments, the individual is ≤ 1 year old.
在一些實施例中,個體介於0至100歲之間。在一些實施例中,個體介於20至90歲之間。在一些實施例中,個體介於30至80歲之間。在一些實施例中,個體介於40至75歲之間。在一些實施例中,個體介於50至70歲之間。在一些實施例中,個體介於40至85歲之間。 C. 基線量測In some embodiments, the individual is between 0 and 100 years old. In some embodiments, the individual is between 20 and 90 years old. In some embodiments, the individual is between 30 and 80 years old. In some embodiments, the individual is between 40 and 75 years old. In some embodiments, the individual is between 50 and 70 years old. In some embodiments, the individual is between 40 and 85 years old. C. Baseline measurement
本文所描述之方法之一些實施例包括自個體獲得基線量測。舉例而言,在一些實施例中,基線量測係在治療個體之前自個體獲得。基線量測之非限制性實例包括基線症狀(例如肝病症狀)量測、基線保護性表型量測、基線目標寡核苷酸(例如mRNA)量測或基線目標蛋白量測。Some embodiments of the methods described herein include obtaining baseline measurements from an individual. For example, in some embodiments, baseline measurements are obtained from an individual prior to treating the individual. Non-limiting examples of baseline measurements include baseline symptom (eg, liver disease symptoms) measurements, baseline protective phenotype measurements, baseline target oligonucleotide (eg, mRNA) measurements, or baseline target protein measurements.
在一些實施例中,基線量測係直接自個體獲得。在一些實施例中,基線量測係藉由觀測,例如藉由觀測個體或個體之組織獲得。在一些實施例中,基線量測係使用成像裝置非侵入性地獲得。在一些實施例中,基線量測係在來自個體之樣本中獲得。在一些實施例中,基線量測係在一或多個組織學組織切片中獲得。在一些實施例中,基線量測係藉由對獲自個體之樣本進行分析,諸如免疫分析、比色分析或螢光分析來獲得。在一些實施例中,基線量測係藉由免疫分析、比色分析或螢光分析來獲得。在一些實施例中,基線量測係藉由PCR獲得。In some embodiments, baseline measurements are obtained directly from the individual. In some embodiments, baseline measurements are obtained by observation, such as by observing an individual or tissue of an individual. In some embodiments, baseline measurements are obtained non-invasively using an imaging device. In some embodiments, baseline measurements are obtained in samples from individuals. In some embodiments, baseline measurements are obtained in one or more histological tissue sections. In some embodiments, the baseline measurement is obtained by analyzing a sample obtained from the individual, such as an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, baseline measurements are obtained by immunoassay, colorimetric analysis, or fluorescence analysis. In some embodiments, baseline measurements are obtained by PCR.
在一些實施例中,基線量測為基線症狀量測。症狀可為與目標寡核苷酸相關之病症之症狀。病症可為肝病。In some embodiments, the baseline measure is a baseline symptom measure. The symptoms may be symptoms of a disorder associated with the target oligonucleotide. The symptoms may be liver disease.
在一些實施例中,基線量測為基線保護性表型量測。保護性表型可保護個體免於患上與目標寡核苷酸相關之病症。保護性表型可與病症之發生率呈負相關。In some embodiments, the baseline measure is a baseline protective phenotype measure. A protective phenotype protects an individual from developing a disorder associated with the target oligonucleotide. The protective phenotype can be inversely related to the incidence of disease.
在一些實施例中,基線量測為基線目標蛋白量測。在一些實施例中,基線目標蛋白量測包含基線目標蛋白含量。在一些實施例中,基線目標蛋白含量指示為每樣本重量之目標蛋白之質量或百分比。在一些實施例中,基線目標蛋白含量指示為每樣本體積之目標蛋白之質量或百分比。在一些實施例中,基線目標蛋白含量指示為樣本內每總蛋白質之目標蛋白之質量或百分比。在一些實施例中,基線目標蛋白量測為基線肝臟或肝細胞目標蛋白量測。在一些實施例中,基線目標蛋白量測為基線循環目標蛋白量測。在一些實施例中,基線目標蛋白量測係藉由分析,諸如免疫分析、比色分析或螢光分析來獲得。In some embodiments, the baseline measurement is a baseline target protein measurement. In some embodiments, the baseline target protein measurement includes baseline target protein content. In some embodiments, baseline target protein content is indicated as mass or percentage of target protein per sample weight. In some embodiments, baseline target protein content is indicated as mass or percentage of target protein per sample volume. In some embodiments, the baseline target protein content is indicated as the mass or percentage of target protein per total protein in the sample. In some embodiments, the baseline target protein measurement is a baseline liver or hepatocyte target protein measurement. In some embodiments, the baseline target protein measurement is a baseline circulating target protein measurement. In some embodiments, baseline target protein measurements are obtained by assays, such as immunoassays, colorimetric assays, or fluorescent assays.
在一些實施例中,基線量測為基線目標mRNA量測。在一些實施例中,基線目標mRNA量測包含基線目標mRNA含量。在一些實施例中,基線目標mRNA含量指示為每樣本重量之目標mRNA之質量或百分比。在一些實施例中,基線目標mRNA含量指示為每樣本體積之目標mRNA之質量或百分比。在一些實施例中,基線目標mRNA含量指示為樣本內每總mRNA之目標mRNA之質量或百分比。在一些實施例中,基線目標mRNA含量指示為樣本內每總核酸之目標mRNA之質量或百分比。在一些實施例中,基線目標mRNA含量相對於樣本內之另一mRNA含量,諸如管家基因之mRNA含量指示。在一些實施例中,基線目標mRNA量測為基線肝臟或肝細胞目標mRNA量測。在一些實施例中,基線目標mRNA量測係藉由分析,諸如聚合酶鏈式反應(polymerase chain reaction;PCR)分析來獲得。在一些實施例中,PCR包含定量PCR (qPCR)。在一些實施例中,PCR包含目標mRNA之反轉錄。In some embodiments, the baseline measurement is a baseline target mRNA measurement. In some embodiments, the baseline target mRNA measurement includes baseline target mRNA content. In some embodiments, baseline target mRNA content is indicated as mass or percentage of target mRNA per sample weight. In some embodiments, baseline target mRNA content is indicated as mass or percentage of target mRNA per sample volume. In some embodiments, the baseline target mRNA content is indicated as the mass or percentage of target mRNA per total mRNA in the sample. In some embodiments, the baseline target mRNA content is indicated as the mass or percentage of target mRNA per total nucleic acid in the sample. In some embodiments, the baseline target mRNA level is indicative of another mRNA level within the sample, such as that of a housekeeping gene. In some embodiments, the baseline target mRNA measurement is a baseline liver or hepatocyte target mRNA measurement. In some embodiments, baseline target mRNA measurements are obtained by analysis, such as polymerase chain reaction (PCR) analysis. In some embodiments, PCR includes quantitative PCR (qPCR). In some embodiments, PCR involves reverse transcription of the target mRNA.
本文所描述之方法之一些實施例包括自個體獲得樣本。在一些實施例中,基線量測係在獲自個體之樣本中獲得。在一些實施例中,樣本係在用本文所描述之組合物投與或治療個體之前自個體獲得。在一些實施例中,基線量測係在向個體投與組合物之前在獲自個體之樣本中獲得。在一些實施例中,樣本係自禁食狀態下之個體獲得。在一些實施例中,樣本係自過夜禁食時段之後的個體獲得。在一些實施例中,樣本係自進食狀態下之個體獲得。Some embodiments of the methods described herein include obtaining a sample from an individual. In some embodiments, baseline measurements are obtained in samples obtained from the individual. In some embodiments, a sample is obtained from an individual prior to administering or treating the individual with a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the individual prior to administration of the composition to the individual. In some embodiments, the sample is obtained from an individual in a fasted state. In some embodiments, the sample is obtained from the individual following an overnight fasting period. In some embodiments, the sample is obtained from an individual in a fed state.
在一些實施例中,樣本包含流體。在一些實施例中,樣本為流體樣本。在一些實施例中,樣本為血液、血漿或血清樣本。在一些實施例中,樣本包含血液。在一些實施例中,樣本為血液樣本。在一些實施例中,樣本為全血樣本。在一些實施例中,血液經分離或離心。在一些實施例中,樣本包含血漿。在一些實施例中,樣本為血漿樣本。在一些實施例中,樣本包含血清。在一些實施例中,樣本為血清樣本。In some embodiments, the sample contains fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma or serum sample. In some embodiments, the sample includes blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, blood is separated or centrifuged. In some embodiments, the sample includes plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample includes serum. In some embodiments, the sample is a serum sample.
在一些實施例中,樣本包含組織。在一些實施例中,樣本為組織樣本。在一些實施例中,樣本包含肝臟組織。在一些實施例中,樣本為肝臟樣本。在一些實施例中,樣本包含肝細胞。在一些實施例中,樣本由肝細胞組成。舉例而言,基線目標mRNA量測或基線目標蛋白量測可在來自患者之肝臟或肝細胞樣本中獲得。在一些實施例中,樣本包含脂肪組織。在一些實施例中,樣本為脂肪樣本。脂肪樣本可包含白色脂肪組織或由其組成。脂肪樣本可包含棕色脂肪組織或由其組成。在一些實施例中,樣本包含腎組織。在一些實施例中,樣本為腎樣本。在一些實施例中,樣本包含心臟組織,諸如心室或心房組織。在一些實施例中,樣本為心臟樣本。在一些實施例中,樣本包含腸組織,諸如小腸組織。在一些實施例中,樣本為小腸樣本。在一些實施例中,樣本包含淋巴結組織,諸如腸系膜淋巴結組織。在一些實施例中,樣本為腸系膜淋巴結樣本。在一些實施例中,樣本包含肌肉組織。在一些實施例中,樣本為肌肉樣本。在一些實施例中,組織樣本包含肝臟、脂肪、腎或心臟組織。在一些實施例中,組織樣本包含棕色脂肪組織、白色脂肪組織、腎組織、腸組織、腸系膜淋巴結或肌肉組織。 D. 效果In some embodiments, the sample includes tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample includes liver tissue. In some embodiments, the sample is a liver sample. In some embodiments, the sample includes hepatocytes. In some embodiments, the sample consists of liver cells. For example, a baseline target mRNA measurement or a baseline target protein measurement may be obtained in a liver or hepatocyte sample from the patient. In some embodiments, the sample includes adipose tissue. In some embodiments, the sample is a fat sample. Fat samples may contain or consist of white adipose tissue. Fat samples may contain or consist of brown adipose tissue. In some embodiments, the sample includes kidney tissue. In some embodiments, the sample is a kidney sample. In some embodiments, the sample includes cardiac tissue, such as ventricular or atrial tissue. In some embodiments, the sample is a heart sample. In some embodiments, the sample includes intestinal tissue, such as small intestine tissue. In some embodiments, the sample is a small intestine sample. In some embodiments, the sample includes lymph node tissue, such as mesenteric lymph node tissue. In some embodiments, the sample is a mesenteric lymph node sample. In some embodiments, the sample includes muscle tissue. In some embodiments, the sample is a muscle sample. In some embodiments, the tissue sample includes liver, adipose, kidney, or heart tissue. In some embodiments, the tissue sample includes brown adipose tissue, white adipose tissue, kidney tissue, intestinal tissue, mesenteric lymph node, or muscle tissue. D. Effect
在一些實施例中,組合物或投與組合物影響量測,諸如相對於基線量測,症狀(例如肝病症狀)量測、保護性表型量測、目標寡核苷酸(例如mRNA)量測或目標蛋白量測(例如肝臟組織目標蛋白含量)。In some embodiments, a composition or administration of a composition affects a measure, such as a measure of symptoms (eg, liver disease symptoms), a measure of a protective phenotype, an amount of a target oligonucleotide (eg, mRNA) relative to a baseline measure or target protein measurement (such as target protein content in liver tissue).
本文所描述之方法之一些實施例包括自個體獲得量測。舉例而言,量測可在治療個體之後自個體獲得。在一些實施例中,量測係在向個體投與組合物之後在獲自個體的第二樣本(諸如本文所描述之流體或組織樣本)中獲得。在一些實施例中,量測為已經治療病症的指示。Some embodiments of the methods described herein include obtaining measurements from an individual. For example, measurements can be obtained from an individual after treating the individual. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the individual after administration of the composition to the individual. In some embodiments, the measurement is an indication that the condition has been treated.
在一些實施例中,量測係直接自個體獲得。在一些實施例中,量測係使用成像裝置非侵入性地獲得。在一些實施例中,量測係在來自個體之第二樣本中獲得。在一些實施例中,量測係在一或多個組織學組織切片中獲得。在一些實施例中,量測係藉由對獲自個體之第二樣本執行分析來獲得。在一些實施例中,量測係藉由分析,諸如本文所描述之分析來獲得。在一些實施例中,分析為免疫分析、比色分析、螢光分析或PCR分析。在一些實施例中,量測係藉由分析,諸如免疫分析、比色分析或螢光分析來獲得。在一些實施例中,量測係藉由PCR獲得。在一些實施例中,量測係藉由組織學獲得。在一些實施例中,量測係藉由觀測來獲得。在一些實施例中,諸如在第3樣本、第4樣本或第五樣本中進行額外量測。In some embodiments, measurements are obtained directly from the individual. In some embodiments, measurements are obtained non-invasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the individual. In some embodiments, measurements are obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing analysis on a second sample obtained from the individual. In some embodiments, measurements are obtained by analysis, such as those described herein. In some embodiments, the assay is an immunoassay, colorimetric assay, fluorescent assay, or PCR assay. In some embodiments, measurements are obtained by analysis, such as immunoassays, colorimetric analyses, or fluorescent analyses. In some embodiments, measurements are obtained by PCR. In some embodiments, measurements are obtained histologically. In some embodiments, measurements are obtained by observation. In some embodiments, additional measurements are performed, such as in the 3rd sample, the 4th sample, or the 5th sample.
在一些實施例中,量測係在投與組合物之後的1小時內、2小時內、3小時內、4小時內、5小時內、6小時內、12小時內、18小時內或24小時內獲得。在一些實施例中,量測係在投與組合物之後的1天內、2天內、3天內、4天內、5天內、6天內或7天內獲得。在一些實施例中,量測係在投與組合物之後的1週內、2週內、3週內、1個月內、2個月內、3個月內、6個月內、1年內、2年內、3年內、4年內或5年內獲得。在一些實施例中,量測係在投與組合物之後的1小時之後、2小時之後、3小時之後、4小時之後、5小時之後、6小時之後、12小時之後、18小時之後或24小時之後獲得。在一些實施例中,量測係在投與組合物之後的1天之後、2天之後、3天之後、4天之後、5天之後、6天之後或7天之後獲得。在一些實施例中,量測係在投與組合物之後的1週之後、2週之後、3週之後、1個月之後、2個月之後、3個月之後、6個月之後、1年之後、2年之後、3年之後、4年或5年之後獲得。In some embodiments, the measurement is within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after administration of the composition obtained within. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after administration of the composition. In some embodiments, the measurement is within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, 1 year after administration of the composition Within, within 2 years, within 3 years, within 4 years or within 5 years. In some embodiments, the measurement is after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after administration of the composition. obtained later. In some embodiments, the measurement is obtained 1 day later, 2 days later, 3 days later, 4 days later, 5 days later, 6 days later, or 7 days later after administration of the composition. In some embodiments, the measurement is after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year after administration of the composition After, after 2 years, after 3 years, after 4 years or after 5 years.
在一些實施例中,相對於基線量測,與個體之病症相關之症狀或參數之量測降低或受影響持續延長時段。在一些實施例中,量測在投與後降低或受影響持續至少約1天、約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天、約21天、約22天、約23天、約24天、約25天、約26天、約27天、約28天、約29天、約30天、約35天、約40天、約45天、約50天、約55天、約60天、約65天、約70天、約75天、約80天、約85天、約90天、約95天、約100天、約105天、約110天、約115天或約120天,或在投與後包含由前述天數中之任兩者限定之範圍的時間範圍。在一些實施例中,量測在投與後降低或受影響持續至少1天、至少2天、至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少26天、至少27天、至少28天、至少29天、至少30天、至少35天、至少40天、至少45天、至少50天、至少55天、至少60天、至少65天、至少70天、至少75天、至少80天、至少85天、至少90天、至少95天、至少100天、至少105天、至少110天、至少115天或至少120天。在一些實施例中,量測在投與後降低或受影響持續不超過1天、不超過2天、不超過3天、不超過4天、不超過5天、不超過6天、不超過7天、不超過8天、不超過9天、不超過10天、不超過11天、不超過12天、不超過13天、不超過14天、不超過15天、不超過16天、不超過17天、不超過18天、不超過19天、不超過20天、不超過21天、不超過22天、不超過23天、不超過24天、不超過25天、不超過26天、不超過27天、不超過28天、不超過29天、不超過30天、不超過35天、不超過40天、不超過45天、不超過50天、不超過55天、不超過60天、不超過65天、不超過70天、不超過75天、不超過80天、不超過85天、不超過90天、不超過95天、不超過100天、不超過105天、不超過110天、不超過115天或不超過120天。在一些實施例中,量測降低或受影響持續至少約5天。在一些實施例中,量測降低或受影響持續至少約10天。在一些實施例中,量測降低或受影響持續至少約15天。在一些實施例中,量測降低或受影響持續至少約20天。在一些實施例中,量測降低或受影響持續至少約25天。在一些實施例中,量測降低或受影響持續至少約30天。在一些實施例中,量測降低或受影響持續至少約40天。在一些實施例中,量測降低或受影響持續至少約50天。在一些實施例中,量測降低或受影響持續至少約60天。在一些實施例中,量測降低或受影響持續至少約70天。在一些實施例中,量測降低或受影響持續至少約80天。在一些實施例中,量測降低或受影響持續至少約90天。在一些實施例中,量測降低或受影響持續至少約100天。在一些實施例中,量測降低或受影響持續至少約110天。在一些實施例中,量測降低或受影響持續至少約120天。與病症相關之症狀或參數之量測之實例可包括目標mRNA量測、目標蛋白量測、生物標記量測或生理量測。量測可在組織(例如肝臟)中或在生物流體(例如血液、血清或血漿)中。In some embodiments, a measure of a symptom or parameter associated with the individual's condition is reduced or affected for an extended period of time relative to a baseline measure. In some embodiments, the measure is reduced or affected for at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, after administration. About 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 35 days, about 40 days, about 45 days, About 50 days, about 55 days, about 60 days, about 65 days, about 70 days, about 75 days, about 80 days, about 85 days, about 90 days, about 95 days, about 100 days, about 105 days, about 110 days, approximately 115 days, or approximately 120 days, or a time range after administration that includes a range bounded by either of the foregoing number of days. In some embodiments, the measure is reduced or affected for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days , at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, at least 65 days, at least 70 days, at least 75 days, at least 80 days, at least 85 days, at least 90 days, at least 95 days, at least 100 days, at least 105 days, at least 110 days , at least 115 days or at least 120 days. In some embodiments, the measure is reduced or affected for no more than 1 day, no more than 2 days, no more than 3 days, no more than 4 days, no more than 5 days, no more than 6 days, no more than 7 days after administration. days, no more than 8 days, no more than 9 days, no more than 10 days, no more than 11 days, no more than 12 days, no more than 13 days, no more than 14 days, no more than 15 days, no more than 16 days, no more than 17 days days, no more than 18 days, no more than 19 days, no more than 20 days, no more than 21 days, no more than 22 days, no more than 23 days, no more than 24 days, no more than 25 days, no more than 26 days, no more than 27 days days, no more than 28 days, no more than 29 days, no more than 30 days, no more than 35 days, no more than 40 days, no more than 45 days, no more than 50 days, no more than 55 days, no more than 60 days, no more than 65 days days, no more than 70 days, no more than 75 days, no more than 80 days, no more than 85 days, no more than 90 days, no more than 95 days, no more than 100 days, no more than 105 days, no more than 110 days, no more than 115 days days or no more than 120 days. In some embodiments, the measurement is reduced or affected for at least about 5 days. In some embodiments, the measurement is reduced or affected for at least about 10 days. In some embodiments, the measurement is reduced or affected for at least about 15 days. In some embodiments, the measurement is reduced or affected for at least about 20 days. In some embodiments, the measurement is reduced or affected for at least about 25 days. In some embodiments, the measurement is reduced or affected for at least about 30 days. In some embodiments, the measurement is reduced or affected for at least about 40 days. In some embodiments, the measurement is reduced or affected for at least about 50 days. In some embodiments, the measurement is reduced or affected for at least about 60 days. In some embodiments, the measurement is reduced or affected for at least about 70 days. In some embodiments, the measurement is reduced or affected for at least about 80 days. In some embodiments, the measurement is reduced or affected for at least about 90 days. In some embodiments, the measurement is reduced or affected for at least about 100 days. In some embodiments, the measurement is reduced or affected for at least about 110 days. In some embodiments, the measurement is reduced or affected for at least about 120 days. Examples of measurements of symptoms or parameters associated with a disorder may include target mRNA measurements, target protein measurements, biomarker measurements, or physiological measurements. Measurements can be in tissue (eg liver) or in biological fluids (eg blood, serum or plasma).
在一些實施例中,相對於基線症狀量測,組合物使症狀量測減少。在一些實施例中,在向個體投與組合物之後量測獲自個體之第二樣本中的減少。在一些實施例中,在向個體投與組合物之後直接量測個體中的減少。在一些實施例中,相對於基線症狀量測,症狀量測降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相對於基線症狀量測,症狀量測降低約10%或更多。在一些實施例中,相對於基線症狀量測,症狀量測降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多。在一些實施例中,相對於基線症狀量測,症狀量測降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相對於基線症狀量測,症狀量測降低不超過約10%。在一些實施例中,相對於基線症狀量測,症狀量測降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,症狀量測降低2.5%、5%、7.5%、10%、20%、30%、40%、50%、60%、70%、80%、90%或100%,或由任何兩個前述百分比限定的範圍。In some embodiments, the composition reduces a symptom measure relative to a baseline symptom measure. In some embodiments, the reduction is measured in a second sample obtained from the individual after administration of the composition to the individual. In some embodiments, the reduction is measured directly in the subject after administration of the composition to the subject. In some embodiments, the symptom measure is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline symptom measure. In some embodiments, the symptom measure is reduced by about 10% or more relative to the baseline symptom measure. In some embodiments, the symptom measure is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more relative to the baseline symptom measure. More, about 70% or more, about 80% or more, about 90% or more. In some embodiments, the symptom measure is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline symptom measure. In some embodiments, the symptom measure is reduced by no more than about 10% relative to the baseline symptom measure. In some embodiments, the symptom measure is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%. In some embodiments, the symptom measure is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or A range bounded by any two of the preceding percentages.
在一些實施例中,相對於基線保護性表型量測,組合物增加保護性表型量測。在一些實施例中,在向個體投與組合物之後量測獲自個體之第二樣本中的增加。在一些實施例中,在向個體投與組合物之後直接量測個體中的增加。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加約10%或更多。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加約100%或更多、增加約250%或更多、增加約500%或更多、增加約750%或更多、或增加約1000%或更多。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加不超過約10%。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%或不超過約100%。在一些實施例中,相對於基線保護性表型量測,保護性表型量測增加不超過約100%、增加不超過約250%、增加不超過約500%、增加不超過約750%、或增加不超過約1000%。在一些實施例中,保護性表型量測增加2.5%、5%、7.5%、10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、250%、500%、750%或1000%,或由任何兩個前述百分比限定的範圍。In some embodiments, the composition increases a protective phenotypic measure relative to a baseline protective phenotypic measure. In some embodiments, the increase is measured in a second sample obtained from the individual after administration of the composition to the individual. In some embodiments, the increase in the subject is measured directly after administration of the composition to the subject. In some embodiments, the protective phenotypic measure increases by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline protective phenotypic measure. In some embodiments, the protective phenotypic measure increases by about 10% or more relative to the baseline protective phenotypic measure. In some embodiments, the protective phenotypic measure increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more relative to the baseline protective phenotypic measure. , about 60% or more, about 70% or more, about 80% or more, about 90% or more. In some embodiments, the protective phenotypic measure increases by about 100% or more, increases by about 250% or more, increases by about 500% or more, increases by about 750% relative to the baseline protective phenotypic measure or more, or an increase of about 1000% or more. In some embodiments, the protective phenotypic measure increases by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline protective phenotypic measure. In some embodiments, the protective phenotypic measure increases by no more than about 10% relative to the baseline protective phenotypic measure. In some embodiments, the protective phenotypic measure increases no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90% or no more than about 100%. In some embodiments, the protective phenotypic measure increases by no more than about 100%, increases by no more than about 250%, increases by no more than about 500%, increases by no more than about 750%, relative to the baseline protective phenotypic measure. or an increase of not more than approximately 1000%. In some embodiments, the protective phenotype measure increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100 %, 250%, 500%, 750% or 1000%, or a range bounded by any two of the foregoing percentages.
在一些實施例中,量測為目標蛋白量測。在一些實施例中,目標蛋白量測包含目標蛋白含量。在一些實施例中,目標蛋白含量指示為每樣本重量之目標蛋白之質量或百分比。在一些實施例中,目標蛋白含量指示為每樣本體積之目標蛋白之質量或百分比。在一些實施例中,目標蛋白含量指示為樣本內每總蛋白質之目標蛋白之質量或百分比。在一些實施例中,目標蛋白量測為細胞(例如肝細胞)目標蛋白量測。在一些實施例中,目標蛋白量測為組織(例如肝臟組織)目標蛋白量測。在一些實施例中,目標蛋白量測為循環目標蛋白量測。在一些實施例中,基線目標蛋白量測係藉由分析,諸如免疫分析、比色分析或螢光分析來獲得。In some embodiments, the measurement is a target protein measurement. In some embodiments, the target protein measurement includes target protein content. In some embodiments, target protein content is indicated as mass or percentage of target protein per sample weight. In some embodiments, target protein content is indicated as mass or percentage of target protein per sample volume. In some embodiments, target protein content is indicated as mass or percentage of target protein per total protein in the sample. In some embodiments, the target protein measurement is a cellular (eg, liver cell) target protein measurement. In some embodiments, the target protein measurement is a tissue (eg, liver tissue) target protein measurement. In some embodiments, the target protein measurement is a circulating target protein measurement. In some embodiments, baseline target protein measurements are obtained by assays, such as immunoassays, colorimetric assays, or fluorescent assays.
在一些實施例中,相對於基線目標蛋白量測結果,組合物使目標蛋白量測減少。在一些實施例中,相對於基線目標蛋白量測,組合物使組織目標蛋白含量(諸如但不限於肝臟組織目標蛋白含量)減少。在一些實施例中,相對於基線目標蛋白量測,組合物使細胞目標蛋白含量(諸如但不限於肝細胞目標蛋白含量)減少。在一些實施例中,相對於基線目標蛋白量測,組合物使循環目標蛋白含量減少。在一些實施例中,在向個體投與組合物之後量測獲自個體之第二樣本中的減少的目標蛋白含量。In some embodiments, the composition reduces a target protein measurement relative to a baseline target protein measurement. In some embodiments, the composition reduces tissue target protein content (such as, but not limited to, liver tissue target protein content) relative to baseline target protein measurements. In some embodiments, the composition reduces cellular target protein content (such as, but not limited to, hepatocyte target protein content) relative to baseline target protein measurements. In some embodiments, the composition reduces circulating target protein levels relative to baseline target protein measurements. In some embodiments, the reduced target protein content is measured in a second sample obtained from the individual after administration of the composition to the individual.
在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低約10%或更多。在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低不超過約10%。在一些實施例中,相對於基線目標蛋白量測,目標蛋白量測降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%、或約100%。在一些實施例中,目標蛋白量測降低2.5%、5%、7.5%、19%、20%、30%、40%、50%、60%、70%、80%、90%、或100%,或由兩個前述百分比中之任一者限定的範圍。目標蛋白量測可降低延長時段。在一些實施例中,目標蛋白量測降低7天、14天、28天、42天、56天、70天、77天、84天、91天、98天、105天或其間的範圍。在一些實施例中,目標蛋白量測降低約7天、約14天、約28天、約42天、約56天、約70天、約77天、約84天、約91天、約98天、約105天或其間的範圍。In some embodiments, the target protein measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline target protein measurement. In some embodiments, the target protein measurement is reduced by about 10% or more relative to the baseline target protein measurement. In some embodiments, the target protein measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% relative to the baseline target protein measurement. or more, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the target protein measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline target protein measurement. In some embodiments, the target protein measurement is reduced by no more than about 10% relative to the baseline target protein measurement. In some embodiments, the target protein measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 60%, or no more than the baseline target protein measurement. More than about 70%, no more than about 80%, no more than about 90%, or about 100%. In some embodiments, the target protein measurement is reduced by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% , or a range defined by either of the two aforementioned percentages. Targeted protein measurement reduces extended time periods. In some embodiments, the target protein measurement is reduced by 7 days, 14 days, 28 days, 42 days, 56 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or a range therebetween. In some embodiments, the target protein measurement decreases by about 7 days, about 14 days, about 28 days, about 42 days, about 56 days, about 70 days, about 77 days, about 84 days, about 91 days, about 98 days , approximately 105 days or a range therebetween.
在一些實施例中,量測為目標mRNA量測。在一些實施例中,目標mRNA量測包含目標mRNA含量。在一些實施例中,目標mRNA含量指示為每樣本重量之目標mRNA之質量或百分比。在一些實施例中,目標mRNA含量指示為每樣本體積之目標mRNA之質量或百分比。在一些實施例中,目標mRNA含量指示為樣本內每總mRNA之目標mRNA之質量或百分比。在一些實施例中,目標mRNA含量指示為樣本內每總核酸之目標mRNA之質量或百分比。在一些實施例中,目標mRNA含量相對於樣本內之另一mRNA含量,諸如管家基因之mRNA含量指示。在一些實施例中,目標mRNA量測係藉由分析,諸如PCR分析來獲得。在一些實施例中,PCR包含qPCR。在一些實施例中,PCR包含目標mRNA之反轉錄。In some embodiments, the measurement is a target mRNA measurement. In some embodiments, the target mRNA measurement includes target mRNA content. In some embodiments, target mRNA content is indicated as mass or percentage of target mRNA per sample weight. In some embodiments, target mRNA content is indicated as mass or percentage of target mRNA per sample volume. In some embodiments, the target mRNA content is indicated as the mass or percentage of target mRNA per total mRNA in the sample. In some embodiments, target mRNA content is indicated as the mass or percentage of target mRNA per total nucleic acid in the sample. In some embodiments, the target mRNA level is indicated relative to another mRNA level within the sample, such as the mRNA level of a housekeeping gene. In some embodiments, target mRNA measurements are obtained by analysis, such as PCR analysis. In some embodiments, PCR includes qPCR. In some embodiments, PCR involves reverse transcription of the target mRNA.
在一些實施例中,相對於基線目標mRNA量測,組合物使目標mRNA量測減少。在一些實施例中,目標mRNA量測係在向個體投與組合物之後在獲自個體之第二樣本中獲得。在一些實施例中,相對於基線目標mRNA含量,組合物使目標mRNA含量減少。在一些實施例中,在向個體投與組合物之後量測獲自個體之第二樣本中的減少的目標mRNA含量。在一些實施例中,第二樣本為第二肝臟樣本。在一些實施例中,第二樣本為第二肝細胞樣本。In some embodiments, the composition reduces a measure of target mRNA relative to a baseline measure of target mRNA. In some embodiments, the target mRNA measurement is obtained in a second sample obtained from the individual after administration of the composition to the individual. In some embodiments, the composition reduces target mRNA levels relative to baseline target mRNA levels. In some embodiments, the reduced target mRNA content is measured in a second sample obtained from the individual after administration of the composition to the individual. In some embodiments, the second sample is a second liver sample. In some embodiments, the second sample is a second hepatocyte sample.
在一些實施例中,相對於基線量測,目標mRNA量測降低約2.5%或更多、約5%或更多、或約7.5%或更多。在一些實施例中,相對於基線目標mRNA量測,目標mRNA量測降低約10%或更多。在一些實施例中,相對於基線目標mRNA量測,目標mRNA量測降低約20%或更多、約30%或更多、約40%或更多、約50%或更多、約60%或更多、約70%或更多、約80%或更多、約90%或更多、或約100%。在一些實施例中,相對於基線目標mRNA量測,目標mRNA量測降低不超過約2.5%、不超過約5%或不超過約7.5%。在一些實施例中,相對於基線目標蛋白量測,目標mRNA量測降低不超過約10%。在一些實施例中,相對於基線目標mRNA量測,目標mRNA量測降低不超過約20%、不超過約30%、不超過約40%、不超過約50%、不超過約60%、不超過約70%、不超過約80%、不超過約90%、或約100%。在一些實施例中,目標mRNA量測降低2.5%、5%、7.5%、10%、20%、30%、40%、50%、60%、70%、80%、90%、100%,或由任何兩個前述百分比限定的範圍。目標mRNA量測可降低延長時段。在一些實施例中,目標mRNA量測降低7天、14天、28天、42天、56天、70天、77天、84天、91天、98天、105天或其間的範圍。在一些實施例中,目標mRNA量測降低約7天、約14天、約28天、約42天、約56天、約70天、約77天、約84天、約91天、約98天、約105天或其間的範圍。一些實施例包括降低除mRNA量測外之RNA量測。 III. 定義 In some embodiments, the target mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline measurement. In some embodiments, the target mRNA measurement is reduced by about 10% or more relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% relative to the baseline target mRNA measurement. or more, about 70% or more, about 80% or more, about 90% or more, or about 100%. In some embodiments, the target mRNA measurement is reduced by no more than about 2.5%, no more than about 5%, or no more than about 7.5% relative to the baseline target mRNA measurement. In some embodiments, the target mRNA measurement is reduced by no more than about 10% relative to the baseline target protein measurement. In some embodiments, the target mRNA measurement is reduced by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 60%, or no more than the baseline target mRNA measurement. More than about 70%, no more than about 80%, no more than about 90%, or about 100%. In some embodiments, the target mRNA measurement is reduced by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or a range bounded by any two of the preceding percentages. Targeted mRNA measurement can reduce the extended period. In some embodiments, the target mRNA measurement decreases by 7 days, 14 days, 28 days, 42 days, 56 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, or a range therebetween. In some embodiments, the target mRNA measurement decreases by about 7 days, about 14 days, about 28 days, about 42 days, about 56 days, about 70 days, about 77 days, about 84 days, about 91 days, about 98 days , approximately 105 days or a range therebetween. Some embodiments include reducing RNA measurements in addition to mRNA measurements. III.Definition _
除非另有定義,否則本文所用之所有技術術語、標記法及其他技術及科學術語意欲具有與一般熟習所主張主題所屬技術者通常所理解相同的含義。在一些情況下,出於清楚起見及/或方便參考,在本文中定義具有通常所理解含義之術語,且本文中包括此類定義不應必然解釋為表示與此項技術中通常所理解存在實質性差異。Unless otherwise defined, all technical terms, notations, and other technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms are defined herein to have commonly understood meanings for clarity and/or convenience of reference, and the inclusion of such definitions herein should not necessarily be construed to mean that there is a meaning that is consistent with what is commonly understood in the art. substantial differences.
在本申請案通篇中,各種實施例可以範圍形式呈現。應理解,範圍形式中之描述僅為了方便及簡潔起見,且不應解釋為對本發明範疇的固定限制。因此,範圍之描述應視為已具體揭示所有可能子範圍以及該範圍內之個別數值。舉例而言,對諸如1至6之範圍的描述應視為已具體揭示諸如1至3、1至4、1至5、2至4、2至6、3至6等子範圍,以及在彼範圍內之個別數值,例如1、2、3、4、5及6。不論範圍之寬度如何,此均適用。Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, descriptions of ranges should be deemed to specifically disclose all possible subranges and individual values within such ranges. For example, description of a range such as 1 to 6 should be deemed to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the like, and therefrom Individual values within a range, such as 1, 2, 3, 4, 5 and 6. This applies regardless of the width of the range.
如在本說明書及申請專利範圍中所使用,除非上下文另外明確規定,否則單數形式「一(a)」、「一(an)」及「該」包括複數個參考物。舉例而言,術語「一個樣本」包括複數個樣本,包括其混合物。As used in this specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a sample" includes a plurality of samples, including mixtures thereof.
一些實例係關於序列。在序列表與本說明書中之揭示內容矛盾之任何程度上,本說明書優先進行。Some examples concern sequences. To the extent that the sequence listing conflicts with the disclosure in this specification, this specification shall prevail.
術語「測定」、「量測」、「評估」、「評定」、「分析(assaying)」及「分析(analyzing)」通常在本文中可互換地用於指量測之形式。該等術語包括測定要素是否存在(例如偵測)。此等術語可包括定量、定性或定量及定性測定。評定可為相對或絕對的。「偵測…之存在」可視上下文而定,包括除測定某物是否存在之外,測定其存在之量。The terms "determine," "measure," "evaluate," "evaluate," "assaying," and "analyzing" are generally used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present (eg, detection). These terms may include quantitative, qualitative, or both quantitative and qualitative determinations. Assessments can be relative or absolute. "Detecting the presence of" depends on the context and includes determining the amount of something present in addition to determining whether it exists.
術語「個體」及「患者」可在本文中互換使用。「個體」可為含有所表現遺傳物質之生物性實體。生物性實體可為植物、動物或微生物,包括例如細菌、病毒、真菌及原生動物。個體可為哺乳動物。哺乳動物可為人類。個體可經診斷或疑似處於疾病之高風險下。在一些情況下,個體未必經診斷或疑似處於疾病之高風險下。The terms "individual" and "patient" are used interchangeably herein. An "individual" may be a biological entity containing expressed genetic material. Biological entities may be plants, animals, or microorganisms, including, for example, bacteria, viruses, fungi, and protozoa. The individual may be a mammal. The mammal may be a human. An individual may be diagnosed or suspected to be at high risk for a disease. In some cases, individuals may not be diagnosed or suspected to be at high risk for a disease.
如本文所用,術語「約」某數字係指該數字加或減該數字之10%。術語「約」某範圍係指該範圍減去其最低值之10%及加其最大值之10%。As used herein, the term "about" a number means that number plus or minus 10% of that number. The term "about" a range means that range minus 10% of its lowest value and plus 10% of its highest value.
如本文中所用,術語「治療(treatment/treating)」參考醫藥方案或用於在接受者中獲得有益或所要結果之其他干預方案來使用。有益或所需結果包括但不限於治療益處及/或預防益處。治療益處可指所治療之症狀或潛在病症的根除或減輕。另外,可藉由根除或減輕與潛在病症相關之生理學症狀中的一或多者以使得在個體中觀測到改善來達成治療益處,儘管該個體可能仍罹患潛在病症。預防作用包括延遲、預防或消除疾病或病狀之出現;延遲或消除疾病或病狀之症狀的發作;減緩、阻止或逆轉疾病或病狀之進展;或其任何組合。對於預防益處,處於罹患特定疾病之風險下的個體或報導疾病之生理學症狀中之一或多者的個體可經受治療,即使可能尚未診斷出此疾病。As used herein, the term "treatment/treating" is used with reference to a pharmaceutical regimen or other intervention regimen used to obtain beneficial or desired results in a recipient. Beneficial or desired results include, but are not limited to, therapeutic benefits and/or preventive benefits. Therapeutic benefit may refer to the eradication or reduction of the symptom or underlying condition being treated. Additionally, therapeutic benefit may be achieved by eradicating or alleviating one or more of the physiological symptoms associated with the underlying condition such that improvement is observed in the individual, although the individual may still suffer from the underlying condition. Preventive action includes delaying, preventing, or eliminating the onset of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; slowing, preventing, or reversing the progression of a disease or condition; or any combination thereof. For preventive benefit, individuals who are at risk for developing a particular disease or who report one or more of the physiological symptoms of the disease may undergo treatment even though the disease may not have been diagnosed.
「治療(Treatment/treating)」可包括就疾病、病症或醫學病狀而言獲得有益或所需結果(包括但不限於治療益處及/或預防益處)的途徑。治療益處可包括例如根除或減輕所治療之潛在病症。另外,治療益處可包括例如根除或減輕與潛在病症相關之生理學症狀中的一或多者以使得在個體中觀測到改善,儘管該個體可能仍罹患潛在病症。在某些實施例中,就預防益處而言,將組合物投與至處於罹患特定疾病之風險下的個體,或投與至報導疾病之生理學症狀中之一或多者的個體,即使可能尚未診斷出此疾病。經由投與本文所描述之化合物治療未必需要涉及醫療專業人士。"Treatment/treating" may include means of obtaining beneficial or desired results (including but not limited to therapeutic benefits and/or preventive benefits) with respect to a disease, disorder or medical condition. Therapeutic benefits may include, for example, eradication or alleviation of the underlying condition being treated. Additionally, therapeutic benefit may include, for example, eradication or alleviation of one or more of the physiological symptoms associated with the underlying condition such that improvement is observed in the individual, although the individual may still suffer from the underlying condition. In certain embodiments, for prophylactic benefit, the composition is administered to an individual at risk of developing a particular disease, or to an individual who reports one or more of the physiological symptoms of the disease, even though it may The disease has not yet been diagnosed. Treatment by administering the compounds described herein does not necessarily require the involvement of a medical professional.
本文所用之章節標題僅出於組織目的且不應解釋為限制所描述之主題。The section headings used in this article are for organizational purposes only and should not be construed as limiting the subject matter described.
術語「C x-y」或「C x-C y」當與諸如烷基、烯基或炔基之化學部分結合使用時意謂包括鏈中含有x至y個碳的基團。舉例而言,術語「C 1-6烷基」係指含有1至6個碳之經取代或未經取代之飽和烴基,包括直鏈烷基及分支鏈烷基。當化學部分經第二化學部分取代時,術語「C x-y」或「C x-C y」並不意謂限制可與化學部分連接之碳原子數。舉例而言,術語「C 1-6烷基」或「C 1至C 6烷基」係指含有1、2、3、4、5或6個碳原子之飽和的經取代或未經取代之烴基,包括直鏈烷基(例如直鏈烷基)及分支鏈烷基,然而C 1-6烷基之任何取代基中可存在許多碳原子。舉例而言,若C 1-6烷基視情況經包含兩個碳原子之第二化學部分取代,則應理解,C 1-6烷基可包括1至8個之間的碳原子。 The term " Cxy " or " Cx - Cy " when used in conjunction with a chemical moiety such as an alkyl, alkenyl or alkynyl group is meant to include groups containing x to y carbons in the chain. For example, the term "C 1-6 alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing 1 to 6 carbons, including straight chain alkyl and branched chain alkyl. When a chemical moiety is substituted by a second chemical moiety, the term "C xy " or "C x -C y " is not meant to limit the number of carbon atoms that may be attached to the chemical moiety. For example, the term "C 1-6 alkyl" or "C 1 to C 6 alkyl" refers to a saturated substituted or unsubstituted alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms. Hydrocarbyl groups include straight chain alkyl groups (eg, straight chain alkyl groups) and branched chain alkyl groups, however many carbon atoms may be present in any substituent of a C 1-6 alkyl group. For example, if the C 1-6 alkyl group is optionally substituted with a second chemical moiety containing two carbon atoms, it is understood that the C 1-6 alkyl group may include between 1 and 8 carbon atoms.
術語「C x-y烯基」及「C x-y炔基」係指經取代或未經取代之不飽和脂族基,其長度及可能之取代與上文所描述之烷基類似,但分別含有至少一個雙鍵或參鍵。 The terms "C xy alkenyl" and "C xy alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups, the length and possible substitutions of which are similar to the alkyl groups described above, but each containing at least one Double bond or parameter bond.
「胺基」係指-NH 2部分。 "Amine" refers to the -NH 2 moiety.
「氰基」係指-CN部分。"Cyano" refers to the -CN moiety.
「硝基」係指-NO 2部分。 "Nitro" refers to the -NO 2 part.
「氧雜」係指-O-部分。"Oxa" means the -O- moiety.
「側氧基」係指=O部分。"Pendant oxy" means the =O moiety.
「硫酮基」係指=S部分。"Thione group" means the =S moiety.
「亞胺基」係指=N-H部分。"Imine" refers to the =N-H moiety.
「肟基(Oximo)」係指=N-OH部分。"Oximo" refers to the =N-OH moiety.
「肼基」係指=N-NH 2部分。 "Hydrazine" refers to the =N-NH 2 moiety.
「烷基」係指僅由碳原子及氫原子組成之完全飽和的直鏈或分支鏈烴部分。在某些實施例中,「烷基」包含一至十五個碳原子(例如C 1-C 15烷基)。在某些實施例中,烷基包含一至十三個碳原子(例如C 1-C 13烷基)。在某些實施例中,烷基包含一至八個碳原子(例如C 1-C 8烷基)。在某些實施例中,烷基包含一至六個碳原子(例如C 1-C 6烷基)。在其他實施例中,烷基包含一至五個碳原子(例如C 1-C 5烷基)。在其他實施例中,烷基包含一至四個碳原子(例如C 1-C 4烷基)。在其他實施例中,烷基包含一至三個碳原子(例如C 1-C 3烷基)。在其他實施例中,烷基包含一至二個碳原子(例如C 1-C 2烷基)。在其他實施例中,烷基包含一個碳原子(例如C 1烷基,例如甲基)。在其他實施例中,烷基包含五至十五個碳原子(例如C 5-C 15烷基)。在其他實施例中,烷基包含五至八個碳原子(例如C 5-C 8烷基)。在其他實施例中,烷基包含二至五個碳原子(例如C 2-C 5烷基)。在其他實施例中,烷基包含三至五個碳原子(例如C 3-C 5烷基)。在其他實施例中,烷基選自甲基、乙基、1-丙基(正丙基)、1-甲基乙基(2-丙基、異丙基)、1-丁基(正丁基)、1-甲基丙基(二級丁基)、2-甲基丙基(異丁基)、1,1-二甲基乙基(三級丁基)及1-戊基(正戊基)。烷基藉由單鍵與分子之其餘部分連接。 "Alkyl" refers to a fully saturated straight or branched hydrocarbon moiety consisting only of carbon atoms and hydrogen atoms. In certain embodiments, "alkyl" contains one to fifteen carbon atoms (eg, C 1 -C 15 alkyl). In certain embodiments, alkyl groups contain one to thirteen carbon atoms (eg, C 1 -C 13 alkyl). In certain embodiments, alkyl groups contain one to eight carbon atoms (eg, C 1 -C 8 alkyl). In certain embodiments, alkyl groups contain one to six carbon atoms (eg, C 1 -C 6 alkyl). In other embodiments, alkyl groups contain one to five carbon atoms (eg, C 1 -C 5 alkyl). In other embodiments, alkyl groups contain one to four carbon atoms (eg, C 1 -C 4 alkyl). In other embodiments, alkyl groups contain one to three carbon atoms (eg, C 1 -C 3 alkyl). In other embodiments, alkyl groups contain one to two carbon atoms (eg, C 1 -C 2 alkyl). In other embodiments, the alkyl group contains one carbon atom (eg, C 1 alkyl, eg, methyl). In other embodiments, the alkyl group contains five to fifteen carbon atoms (eg, C 5 -C 15 alkyl). In other embodiments, alkyl groups contain five to eight carbon atoms (eg, C 5 -C 8 alkyl). In other embodiments, alkyl groups contain two to five carbon atoms (eg, C 2 -C 5 alkyl). In other embodiments, the alkyl group contains three to five carbon atoms (eg, C 3 -C 5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (2-propyl, isopropyl), 1-butyl (n-butyl) base), 1-methylpropyl (secondary butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl) and 1-pentyl (normal Pentyl). The alkyl group is connected to the rest of the molecule by a single bond.
「胺基烷基」係指經由氮原子鍵結之形式-N(H)(烷基)或N(烷基)(烷基)的部分,其中當該部分為N(烷基)(烷基)時,鍵結至氮之兩個烷基可為相同烷基或不同烷基。"Aminoalkyl" means a moiety of the form -N(H)(alkyl) or N(alkyl)(alkyl) bonded through a nitrogen atom, where when the moiety is N(alkyl)(alkyl) ), the two alkyl groups bonded to the nitrogen may be the same alkyl group or different alkyl groups.
「烷氧基」係指具有式-O-烷基,經由氧原子鍵結的部分,其中烷基為如上文所定義之烷基鏈。"Alkoxy" means a moiety having the formula -O-alkyl, bonded through an oxygen atom, where alkyl is an alkyl chain as defined above.
「烯基」係指僅由碳原子及氫原子組成,含有至少一個碳-碳雙鍵之直鏈或分支鏈烴部分。在某些實施例中,烯基包含二至十二個碳原子。在某些實施例中,烯基包含二至八個碳原子。在其他實施例中,烯基包含二至四個碳原子。烯基藉由單鍵連接於分子之其餘部分,例如乙烯基(ethenyl)(亦即乙烯基(vinyl))、丙-1-烯基(亦即烯丙基)、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基及其類似基團。"Alkenyl" refers to a linear or branched hydrocarbon moiety consisting only of carbon atoms and hydrogen atoms and containing at least one carbon-carbon double bond. In certain embodiments, alkenyl groups contain two to twelve carbon atoms. In certain embodiments, alkenyl groups contain two to eight carbon atoms. In other embodiments, alkenyl groups contain two to four carbon atoms. Alkenyl groups are connected to the rest of the molecule by single bonds, such as ethenyl (also known as vinyl), prop-1-enyl (also known as allyl), but-1-enyl, Pent-1-enyl, pent-1,4-dienyl and similar groups.
「炔基」係指僅由碳原子及氫原子組成,含有至少一個碳-碳三鍵,具有二至十二個碳原子且視情況進一步包含至少一個碳-碳雙鍵之直鏈或分支鏈烴部分。在某些實施例中,炔基包含二至八個碳原子。在其他實施例中,炔基包含二至六個碳原子。在其他實施例中,炔基包含二至四個碳原子。炔基藉由單鍵連接於分子之其餘部分,例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及其類似基團。"Alkynyl" means a straight or branched chain consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms, and optionally further containing at least one carbon-carbon double bond hydrocarbon part. In certain embodiments, alkynyl groups contain two to eight carbon atoms. In other embodiments, alkynyl groups contain two to six carbon atoms. In other embodiments, alkynyl groups contain two to four carbon atoms. Alkynyl groups are connected to the rest of the molecule by single bonds, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and similar groups.
「伸烷基」或「伸烷基鏈」係指線性(例如直鏈)或分支鏈的二價烴部分。「伸烷基」或「伸烷基鏈」可將分子之一部分與第二部分連接。「伸烷基」或「伸烷基鏈」僅僅由碳原子及氫原子組成(可指定伸烷基經一或多個包含除氫以外之原子(諸如N、O及S)的取代基取代)。「伸烷基」或「伸烷基鏈」可能不含不飽和性(不管伸烷基與分子之其餘部分之連接點)。在某些實施例中,「伸烷基」或「伸烷基鏈」包含一至十二個碳原子,例如亞甲基、伸乙基、伸丙基、伸正丁基及其類似者。伸烷基鏈可經由單鍵與分子之部分連接且經由單鍵與第二部分連接。伸烷基鏈與分子之其餘部分及與第二部分之連接點可經由伸烷基鏈中之一個碳或經由伸烷基內之任何兩個碳。在某些實施例中,伸烷基包含一至八個碳原子(例如C 1-C 8伸烷基)。在其他實施例中,伸烷基包含一至五個碳原子(例如C 1-C 5伸烷基)。在其他實施例中,伸烷基包含一至四個碳原子(例如C 1-C 4伸烷基)。在其他實施例中,伸烷基包含一至三個碳原子(例如C 1-C 3伸烷基)。在其他實施例中,伸烷基包含一至二個碳原子(例如C 1-C 2伸烷基)。在其他實施例中,伸烷基包含一個碳原子(例如C 1亞烷基)。在其他實施例中,伸烷基包含五至八個碳原子(例如C 5-C 8伸烷基)。在其他實施例中,伸烷基包含二至五個碳原子(例如C 2-C 5伸烷基)。在其他實施例中,伸烷基包含三至五個碳原子(例如C 3-C 5伸烷基)。 "Alkylene" or "alkylene chain" refers to a linear (eg straight chain) or branched chain divalent hydrocarbon moiety. An "alkylene group" or "alkylene chain" can connect one part of a molecule to a second part. An "alkylene group" or "alkylene chain" consists solely of carbon atoms and hydrogen atoms (alkylene groups may be specified to be substituted with one or more substituents containing atoms other than hydrogen, such as N, O, and S). . An "alkylene group" or "alkylene chain" may contain no unsaturation (regardless of the point of attachment of the alkylene group to the rest of the molecule). In certain embodiments, an "alkylene group" or "alkylene chain" contains one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butyl, and the like. The alkylene chain may be connected to one part of the molecule via a single bond and to a second part via a single bond. The point of attachment of the alkylene chain to the remainder of the molecule and to the second moiety may be via one carbon in the alkylene chain or via any two carbons within the alkylene group. In certain embodiments, an alkylene group contains one to eight carbon atoms (eg, C 1 -C 8 alkylene). In other embodiments, the alkylene group contains one to five carbon atoms (eg, C 1 -C 5 alkylene). In other embodiments, the alkylene group contains one to four carbon atoms (eg, C 1 -C 4 alkylene). In other embodiments, the alkylene group contains one to three carbon atoms (eg, C 1 -C 3 alkylene). In other embodiments, the alkylene group contains one to two carbon atoms (eg, C 1 -C 2 alkylene). In other embodiments, the alkylene group contains one carbon atom (eg, C 1 alkylene). In other embodiments, the alkylene group contains five to eight carbon atoms (eg, C 5 -C 8 alkylene). In other embodiments, the alkylene group contains two to five carbon atoms (eg, C 2 -C 5 alkylene). In other embodiments, the alkylene group contains three to five carbon atoms (eg, C 3 -C 5 alkylene).
「伸烯基」或「伸烯基鏈」係指線性(例如直鏈)或分支鏈的二價烴部分。「伸烯基」或「伸烯基鏈」可將分子之一部分與第二部分連接。「伸烯基」或「伸烯基鏈」僅僅由碳原子及氫原子組成(可指定伸烯基經一或多個包含除氫以外之原子(諸如N、O及S)的取代基取代)。「伸烯基」或「伸烯基鏈」包含至少一個碳-碳雙鍵。在某些實施例中,「伸烯基」或「伸烯基鏈」包含二至十二個碳原子。伸烯基鏈可經由單鍵與分子之部分連接且經由單鍵與第二部分連接。伸烯基鏈與分子之其餘部分及與第二部分之連接點可經由伸烯基鏈中之一個碳或經由伸烯基鏈內之任何兩個碳。在某些實施例中,伸烯基包含二至八個碳原子(例如C 2-C 8伸烯基)。在其他實施例中,伸烯基包含二至五個碳原子(例如C 2-C 5伸烯基)。在其他實施例中,伸烯基包含二至四個碳原子(例如C 2-C 4伸烯基)。在其他實施例中,伸烯基包含二至三個碳原子(例如C 2-C 3伸烯基)。在其他實施例中,伸烯基包含五至八個碳原子(例如C 5-C 8伸烯基)。在其他實施例中,伸烯基包含二至五個碳原子(例如C 2-C 5伸烯基)。在其他實施例中,伸烯基包含三至五個碳原子(例如C 3-C 5伸烯基)。 "Alkenylene" or "alkenylene chain" refers to a linear (eg straight chain) or branched chain divalent hydrocarbon moiety. An "alkenylene group" or "alkenylene chain" can connect one part of a molecule to a second part. An "alkenylene group" or "alkenylene chain" consists solely of carbon atoms and hydrogen atoms (alkenylene groups may be specified to be substituted with one or more substituents containing atoms other than hydrogen, such as N, O, and S). . "Alkenyl" or "alkenyl chain" contains at least one carbon-carbon double bond. In certain embodiments, an "alkenylene group" or "alkenylene chain" contains from two to twelve carbon atoms. The alkenylene chain may be connected to one part of the molecule via a single bond and to a second part via a single bond. The point of attachment of the alkenylene chain to the remainder of the molecule and to the second moiety may be via one carbon in the alkenylene chain or via any two carbons within the alkenylene chain. In certain embodiments, alkenylene contains two to eight carbon atoms (eg, C 2 -C 8 alkenyl). In other embodiments, the alkenylene group contains two to five carbon atoms (eg, C 2 -C 5 alkenyl). In other embodiments, the alkenylene group contains two to four carbon atoms (eg, C 2 -C 4 alkenylene). In other embodiments, the alkenylene group contains two to three carbon atoms (eg, C 2 -C 3 alkenylene). In other embodiments, the alkenylene group contains five to eight carbon atoms (eg, C 5 -C 8 alkenylene). In other embodiments, the alkenylene group contains two to five carbon atoms (eg, C 2 -C 5 alkenyl). In other embodiments, the alkenylene group contains three to five carbon atoms (eg, C 3 -C 5 alkenylene).
「伸炔基」或「伸炔基鏈」係指線性(例如直鏈)或分支鏈的二價烴部分。「伸炔基」或「伸炔基鏈」可將分子之一部分與第二部分連接。「伸炔基」或「伸炔基鏈」僅僅由碳及氫組成(可指定伸炔基經一或多個包含除氫以外之原子(諸如N、O及S)的取代基取代)。「伸炔基」或「伸炔基鏈」包含至少一個碳-碳三鍵。在某些實施例中,「伸炔基」或「伸炔基鏈」包含二至十二個碳原子。伸炔基鏈可經由單鍵與分子之部分連接且經由單鍵與第二部分連接。伸炔基鏈與分子之其餘部分及與第二部分之連接點可經由伸炔基鏈中之一個碳或經由伸炔基鏈內之任何兩個碳。在某些實施例中,伸炔基包含二至八個碳原子(例如C 2-C 8伸炔基)。在其他實施例中,伸炔基包含二至五個碳原子(例如C 2-C 5伸炔基)。在其他實施例中,伸炔基包含二至四個碳原子(例如C 2-C 4伸炔基)。在其他實施例中,伸炔基包含二至三個碳原子(例如C 2-C 3伸炔基)。在其他實施例中,伸炔基包含兩個碳原子(例如C 2伸炔基)。在其他實施例中,伸炔基包含五至八個碳原子(例如C 5-C 8伸炔基)。在其他實施例中,伸炔基包含三至五個碳原子(例如C 3-C 5伸炔基)。 "Alkynyl" or "alkynyl chain" refers to a linear (eg, straight chain) or branched chain divalent hydrocarbon moiety. An "alkynyl" or "alkynyl chain" can connect one part of a molecule to a second part. An "alkynyl group" or "alkynyl chain" consists solely of carbon and hydrogen (alkynyl groups may be specified to be substituted with one or more substituents containing atoms other than hydrogen, such as N, O, and S). "Alkynyl" or "alkynyl chain" contains at least one carbon-carbon triple bond. In certain embodiments, an "alkynyl group" or "alkynyl chain" contains two to twelve carbon atoms. The alkynylene chain may be connected to one part of the molecule via a single bond and to a second part via a single bond. The point of attachment of the alkynyl chain to the rest of the molecule and to the second part may be via one carbon in the alkynyl chain or via any two carbons within the alkynyl chain. In certain embodiments, an alkynylene group contains two to eight carbon atoms (eg, C 2 -C 8 alkynylene). In other embodiments, the alkynylene group contains two to five carbon atoms (eg, C 2 -C 5 alkynylene). In other embodiments, the alkynylene group contains two to four carbon atoms (eg, C 2 -C 4 alkynylene). In other embodiments, the alkynylene group contains two to three carbon atoms (eg, C 2 -C 3 alkynylene). In other embodiments, the alkynylene group contains two carbon atoms (eg, C alkynylene ). In other embodiments, the alkynylene group contains five to eight carbon atoms (eg, C 5 -C 8 alkynylene). In other embodiments, the alkynylene group contains three to five carbon atoms (eg, C 3 -C 5 alkynylene).
如本文所用,術語「碳環」係指飽和、不飽和環或芳族環,其中環之各原子為碳原子。碳環包括3至10員單環、5至12員雙環、5至12員螺雙環及5至12員橋聯環。雙環碳環之各環可選自飽和、不飽和環及芳族環。在一例示性實施例中,芳族環(例如苯基)可與飽和或不飽和環,例如環己烷、環戊烷或環己烯稠合。在價數准許之情況下,雙環碳環包括飽和雙環、不飽和雙環及芳族雙環之任何組合。雙環碳環進一步包括螺雙環,諸如螺戊烷。雙環碳環包括環大小之任何組合,諸如3-3螺環系統、4-4螺環系統、4-5稠環系統、5-5稠環系統、5-6稠環系統、6-6稠環系統、5-7稠環系統、6-7稠環系統、5-8稠環系統及6-8稠環系統。例示性碳環包括環戊基、環己基、環己烯基、金剛烷基、苯基、二氫茚基、萘基及雙環[1.1.1]戊基。「碳環」可包括「芳基」及「環烷基」。As used herein, the term "carbocycle" refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbon rings include single rings with 3 to 10 members, double rings with 5 to 12 members, spiro double rings with 5 to 12 members, and bridged rings with 5 to 12 members. Each ring of the bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings and aromatic rings. In an exemplary embodiment, an aromatic ring (eg, phenyl) can be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valency permits, bicyclic carbocyclic rings include any combination of saturated bicyclic rings, unsaturated bicyclic rings and aromatic bicyclic rings. Bicyclic carbocycles further include spirobicyclos, such as spiropentane. Bicyclic carbocycles include any combination of ring sizes, such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems Ring system, 5-7 fused ring system, 6-7 fused ring system, 5-8 fused ring system and 6-8 fused ring system. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indenyl, naphthyl, and bicyclo[1.1.1]pentyl. "Carbocycle" may include "aryl" and "cycloalkyl".
術語「芳基」係指芳族單環或芳族多環烴環系統。芳族單環或多環烴環系統僅含有氫及碳,以及五至十八個碳原子,其中環系統中之至少一個環為芳族,亦即根據Hückel理論,其含有環狀、非定域(4n+2) π電子系統。衍生芳基之環系統包括但不限於諸如苯、茀、茚烷、茚、四氫萘及萘之基團。在一些實施例中,芳基取代基帶正電或帶負電。在一些實施例中,芳基取代基為中性的。在一些實施例中,芳基取代基為兩性離子;或者或另外,在一些實施例中,芳基取代基不帶電。在一些實施例中,芳基取代基不攜帶電荷。在一些實施例中,芳基取代基不攜帶淨電荷。在一些實施例中,芳基取代基不攜帶淨電荷且不為兩性離子。The term "aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon, and five to eighteen carbon atoms, of which at least one ring in the ring system is aromatic, that is, according to Hückel's theory, it contains cyclic, irregular Domain (4n+2) π electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, benzene, indene, indene, tetralin, and naphthalene. In some embodiments, aryl substituents are positively or negatively charged. In some embodiments, aryl substituents are neutral. In some embodiments, the aryl substituent is a zwitterion; alternatively or additionally, in some embodiments, the aryl substituent is uncharged. In some embodiments, aryl substituents carry no charge. In some embodiments, aryl substituents carry no net charge. In some embodiments, aryl substituents carry no net charge and are not zwitterionic.
術語「環烷基」係指其中環之各原子為碳的飽和環。環烷基可包括單環及多環,諸如3至10員單環、5至12員雙環、5至12員螺雙環及5至12員橋聯環。在某些實施例中,環烷基包含三至十個碳原子。在其他實施例中,環烷基包含五至七個碳原子。環烷基可藉由單鍵與分子之其餘部分連接。單環環烷基之實例包括例如環丙基、環丁基、環戊基、環己基、環庚基及環辛基。多環環烷基包括例如金剛烷基、螺戊烷、降莰基(亦即雙環[2.2.1]庚基)、十氫萘基、7,7二甲基雙環[2.2.1]庚基、雙環[1.1.1]戊基及其類似者。The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl groups may include monocyclic and polycyclic rings, such as 3 to 10 membered monocyclic rings, 5 to 12 membered bicyclic rings, 5 to 12 membered spirobicyclic rings, and 5 to 12 membered bridged rings. In certain embodiments, cycloalkyl groups contain three to ten carbon atoms. In other embodiments, cycloalkyl contains five to seven carbon atoms. A cycloalkyl group can be connected to the rest of the molecule through a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, spiropentane, norbornyl (i.e. bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7dimethylbicyclo[2.2.1]heptyl , bicyclo[1.1.1]pentyl and the like.
術語「環烯基」係指其中環之各原子為碳且兩個環碳之間存在至少一個雙鍵的飽和環。環烯基可包括單環及多環,諸如3至10員單環、6至12員雙環及5至12員橋聯環。在其他實施例中,環烯基包含五至七個碳原子。環烯基可藉由單鍵與分子之其餘部分連接。單環環烯基之實例包括例如環戊烯基、環己烯基、環庚烯基及環辛烯基。The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between the two ring carbons. Cycloalkenyl groups may include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, cycloalkenyl contains five to seven carbon atoms. The cycloalkenyl group can be connected to the rest of the molecule through a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
術語「鹵基」或者「鹵素」或「鹵離子(halide)」意謂氟、氯、溴或碘。在一些實施例中,鹵基為氟、氯或溴。The term "halo" or "halogen" or "halide" means fluorine, chlorine, bromine or iodine. In some embodiments, the halo group is fluorine, chlorine, or bromine.
術語「鹵烷基」係指如上文所定義之烷基,其經一或多個鹵基取代,例如三氟甲基、二氯甲基、溴甲基、2,2,2-三氟乙基、1-氯甲基-2-氟乙基及其類似者。在一些實施例中,鹵烷基之烷基部分視情況如本文所描述進一步經取代。The term "haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halo groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl base, 1-chloromethyl-2-fluoroethyl and the like. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.
如本文所用,術語「雜環」係指包含一或多個雜原子之飽和、不飽和環或芳族環。例示性雜原子包括N、O、Si、P、B及S原子。雜環包括3至10員單環、6至12員雙環、5至12員螺雙環及5至12員橋聯環。在價數准許之情況下,雙環雜環包括飽和雙環、不飽和雙環及芳族雙環之任何組合。在一例示性實施例中,芳族環(例如吡啶基)可與飽和或不飽和環,例如環己烷、環戊烷、𠰌啉、哌啶或環己烯稠合。雙環雜環包括環大小之任何組合,諸如4-5稠環系統、5-5稠環系統、5-6稠環系統、6-6稠環系統、5-7稠環系統、6-7稠環系統、5-8稠環系統及6-8稠環系統。雙環雜環進一步包括螺雙環,例如5至12員螺雙環,諸如2-氧雜-6-氮雜螺[3.3]庚烷。「雜環」可包括「雜芳基」及「雜環烷基」。As used herein, the term "heterocycle" refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic rings include 3 to 10 membered monocyclic rings, 6 to 12 membered bicyclic rings, 5 to 12 membered spirobicyclic rings, and 5 to 12 membered bridged rings. Bicyclic heterocycles include any combination of saturated bicyclic rings, unsaturated bicyclic rings, and aromatic bicyclic rings, as long as the valency permits. In an exemplary embodiment, an aromatic ring (eg, pyridyl) can be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, cyclohexane, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused Ring system, 5-8 fused ring system and 6-8 fused ring system. Bicyclic heterocycles further include spirobicyclos, such as 5 to 12 membered spirobicyclos, such as 2-oxa-6-azaspiro[3.3]heptane. "Heterocycle" may include "heteroaryl" and "heterocycloalkyl".
術語「雜芳基」係指衍生自5至18員芳環基團之基團,其包含二至十七個碳原子及一至六個選自氮、氧及硫之雜原子。如本文所用,雜芳基為單環、雙環、三環或四環系統,其中環系統中之至少一個環為芳族,亦即根據Hückel理論,其含有環狀、非定域(4n+2) π電子系統。雜芳基包括稠合或橋聯環系統。雜芳基中之雜原子視情況經氧化。一或多個氮原子(若存在)視情況經四級銨化。雜芳基經由環之任何原子與分子之其餘部分連接。雜芳基之實例包括但不限於氮呯基、吖啶基、苯并咪唑基、苯并吲哚基、1,3-苯并二氧雜環戊烯基、苯并呋喃基、苯并㗁唑基、苯并[d]噻唑基、苯并噻二唑基、苯并[ b][1,4]二㗁呯基、苯并[b][1,4]㗁 𠯤基、1,4-苯并二㗁烷基、苯并萘并呋喃基、苯并㗁唑基、苯并二氧雜環戊烯基、苯并二氧雜環己烯基、苯并哌喃基、苯并哌喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(benzothienyl/benzothiophenyl)、苯并噻吩并[3,2-d]嘧啶基、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、㖕啉基、環戊并[d]嘧啶基、6,7-二氫-5H-環戊并[4,5]噻吩并[2,3-d]嘧啶基、5,6-二氫苯并[h]喹唑啉基、5,6-二氫苯并[h]㖕啉基、6,7-二氫-5H-苯并[6,7]環庚[1,2-c]嗒𠯤基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、呋喃并[3,2-c]吡啶基、5,6,7,8,9,10-六氫環辛并[d]嘧啶基、5,6,7,8,9,10-六氫環辛并[d]嗒𠯤基、5,6,7,8,9,10-六氫環辛并[d]吡啶基、異噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、異吲哚基、吲哚啉基、異吲哚啉基、異喹啉基、吲基、異㗁唑基、5,8-甲橋-5,6,7,8-二氫喹唑啉基、㖠啶基、1,6-㖠啶酮基、㗁二唑基、2-側氧基氮呯基、㗁唑基、環氧乙基、5,6,6a,7,8,9,10,10a-八氫苯并[h]喹唑啉基、1-苯基-1 H-吡咯基、啡𠯤基、啡噻𠯤基、啡㗁𠯤基、呔𠯤基、喋啶基、嘌呤基、吡咯基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡𠯤基、嘧啶基、嗒𠯤基、吡咯基、喹唑啉基、喹㗁啉基、喹啉基、異喹啉基、四氫喹啉基、5,6,7,8-二氫喹唑啉基、5,6,7,8-四氫苯并[4,5]噻吩并[2,3-d]嘧啶基、6,7,8,9-四氫-5H-環庚[4,5]噻吩并[2,3-d]嘧啶基、5,6,7,8-四氫吡啶并[4,5-c]嗒𠯤基、噻唑基、噻二唑基、三唑基、四唑基、三𠯤基、噻吩并[2,3-d]嘧啶基、噻吩并[3,2-d]嘧啶基、噻吩并[2,3-c]吡啶基及噻吩基(thiophenyl) (亦即噻吩基(thienyl))。 The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing from two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one ring in the ring system is aromatic, that is, according to Hückel's theory, it contains cyclic, nonlocalized (4n+2 ) π electron system. Heteroaryl groups include fused or bridged ring systems. Heteroatoms in heteroaryl groups are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryl groups include, but are not limited to, azumabyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzodizoyl Azolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[ b ][1,4]dimethacryl, benzo[b][1,4]㗁𠯤yl, 1,4 -Benzodisyl, benzonaphthofuryl, benzoxazolyl, benzodioxolyl, benzodioxenyl, benzopyranyl, benzopiperyl Benzofuranone group, benzofuranyl group, benzofuranone group, benzothienyl/benzothiophenyl group, benzothieno[3,2-d]pyrimidinyl group, benzotriazolyl group, benzo[4, 6]Imidazo[1,2-a]pyridyl, carbazolyl, oxolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]oxolinyl, 6,7-dihydro-5H- Benzo[6,7]cyclohept[1,2-c]pyridyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, furo[3,2-c]pyridyl , 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidinyl, 5, 6,7,8,9,10-Hexahydrocycloocta[d]pyridyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, Isoindolinyl, isoquinolinyl, indolinyl base, isothiazolyl, 5,8-methyl bridge-5,6,7,8-dihydroquinazolinyl, aridinyl, 1,6-ridinonyl, dioxadiazolyl, 2-side Oxyazolyl, oxazolyl, epoxyethyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl- 1H -Pyrrolyl, phenanthrophyllyl, phenanthro[3,4-d]pyrimidinyl, pyrrolyl, purinyl, pyrrolyl, pyridinyl, pyrazolo[3,4-d]pyrimidinyl base, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinoyl, Quinolyl, isoquinolyl, tetrahydroquinolyl, 5,6,7,8-dihydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[ 2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohept[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydro Hydropyrido[4,5-c]pyrimidinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, trizoyl, thieno[2,3-d]pyrimidinyl, thieno[3 ,2-d]pyrimidinyl, thieno[2,3-c]pyridyl and thienyl (thienyl) (also known as thienyl).
一或多個氮原子(若存在)可視情況經四級銨化。在一些實施例中,雜環取代基帶正電或帶負電。在一些實施例中,雜環取代基為中性的。在一些實施例中,雜環取代基為兩性離子;或者或另外,在一些實施例中,雜環取代基不帶電。在一些實施例中,雜環取代基不攜帶電荷。在一些實施例中,雜環取代基不攜帶淨電荷。在一些實施例中,雜環取代基不攜帶淨電荷且不為兩性離子。One or more nitrogen atoms, if present, may optionally be quaternized. In some embodiments, heterocyclic substituents are positively or negatively charged. In some embodiments, heterocyclic substituents are neutral. In some embodiments, the heterocyclic substituent is a zwitterion; alternatively or additionally, in some embodiments, the heterocyclic substituent is uncharged. In some embodiments, heterocyclic substituents carry no charge. In some embodiments, heterocyclic substituents carry no net charge. In some embodiments, the heterocyclic substituents carry no net charge and are not zwitterionic.
術語「雜環烷基」係指具有碳原子及至少一個雜原子之飽和環。例示性雜原子包括N、O、Si、P、B及S原子。雜環烷基可包括單環及多環,諸如3至10員單環、6至12員雙環、5至12員螺雙環及5至12員橋聯環。雜環烷基中之雜原子視情況經氧化。一或多個氮原子(若存在)視情況經四級銨化。雜環烷基在價態准許下經由雜環烷基之任何原子(諸如雜環烷基之任何碳或氮原子)與分子之其餘部分連接。雜環烷基之實例包括但不限於二氧雜環戊烷基、噻吩基[1,3]二噻烷基、十氫異喹啉基、咪唑啉基、咪唑啶基、異噻唑啶基、異㗁唑啶基、𠰌啉基、八氫吲哚基、八氫異吲哚基、2-側氧基哌𠯤基、2-側氧基哌啶基、2-側氧基吡咯啶基、㗁唑啶基、哌啶基、哌𠯤基、4-哌啶酮基、吡咯啶基、吡唑啶基、啶基、噻唑啶基、四氫呋喃基、三噻烷基、四氫哌喃基、硫代𠰌啉基、噻𠰌啉基、1-側氧基-硫代𠰌啉基、2-氧雜-6-氮雜螺[3.3]庚烷及1,1-二側氧基-硫代𠰌啉基。在一些實施例中,雜環烷基包含一個雜原子。在一些實施例中,雜環烷基包含一個選自N、O及S之雜原子。在一些實施例中,雜環烷基包含多個雜原子。在一些實施例中,雜環烷基包含多個選自N、O及S之雜原子。The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl groups may include monocyclic and polycyclic rings, such as 3 to 10 membered monocyclic rings, 6 to 12 membered bicyclic rings, 5 to 12 membered spirobicyclic rings, and 5 to 12 membered bridged rings. Heteroatoms in heterocycloalkyl groups are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl group is attached to the remainder of the molecule via any atom of the heterocycloalkyl group, such as any carbon or nitrogen atom of the heterocycloalkyl group, as the valence state permits. Examples of heterocycloalkyl include, but are not limited to, dioxolanyl, thienyl[1,3]disthianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, Isoethazolidinyl, 𠰌linyl, octahydroindolyl, octahydroisoindolyl, 2-side oxypiperidinyl, 2-side oxypiperidinyl, 2-side oxypyrrolidinyl, oxazolidinyl, piperidinyl, piperidinyl, 4-piperidinonyl, pyrrolidinyl, pyrazoridinyl, Aldyl, thiazolidinyl, tetrahydrofuranyl, trithialkyl, tetrahydropyranyl, thio𠰌linyl, thioxa-linyl, 1-side oxy-thioxa-6 -Azaspiro[3.3]heptane and 1,1-dilateral oxy-thio𠰌linyl group. In some embodiments, heterocycloalkyl contains one heteroatom. In some embodiments, heterocycloalkyl contains a heteroatom selected from N, O, and S. In some embodiments, heterocycloalkyl groups contain multiple heteroatoms. In some embodiments, heterocycloalkyl groups contain multiple heteroatoms selected from N, O, and S.
術語「雜環烯基」係指具有碳原子及至少一個雜原子且兩個環碳之間存在至少一個雙鍵的不飽和環。雜環烯基不包括雜芳基環。例示性雜原子包括N、O、Si、P、B及S原子。雜環烯基可包括單環及多環,諸如3至10員單環、6至12員雙環及5至12員橋聯環。在其他實施例中,雜環烯基包含五至七個環原子。雜環烯基可藉由單鍵與分子之其餘部分連接。單環環烯基之實例包括例如吡咯啉(二氫吡咯)、吡唑啉(二氫吡唑)、咪唑啉(二氫咪唑)、三唑啉(二氫三唑)、二氫呋喃、二氫噻吩、㗁唑啉(二氫㗁唑)、異㗁唑啉(二氫異㗁唑)、噻唑啉(二氫噻唑)、異噻唑啉(二氫異噻唑)、㗁二唑啉(二氫㗁二唑)、噻二唑啉(二氫噻二唑)、二氫吡啶、四氫吡啶、二氫嗒𠯤、四氫嗒𠯤、二氫嘧啶、四氫嘧啶、二氫吡𠯤、四氫吡𠯤、哌喃、二氫哌喃、硫代哌喃、二氫噻喃、戴奧辛(dioxine)、二氫戴奧辛、㗁𠯤、二氫㗁𠯤、噻𠯤及二氫噻𠯤。The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom and at least one double bond between the two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl groups may include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, heterocycloalkenyl contains five to seven ring atoms. The heterocyclenyl group can be connected to the rest of the molecule through a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydrimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrofuran, Hydrothiophene, isothiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), tetrazoline (dihydrothiazoline) thiadiazole), thiadiazoline (dihydrothiazoline), dihydropyridine, tetrahydropyridine, dihydropyridine, tetrahydropyridine, dihydropyrimidine, ectoine, dihydropyridine, tetrahydropyridine Pyridoxine, dihydropyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxin, dihydropyran, dihydropyran, thiopyran and dihydrothiocin.
術語「經取代」係指在化合物之一或多個碳或可取代的雜原子(例如,NH或NH 2)上具有置換氫之取代基的部分。應理解,「取代」或「經取代」包括暗示限制條件:此類取代與經取代原子及取代基之准許價數一致,且取代產生穩定化合物,亦即不自發地進行諸如藉由重排、環化、消除等進行之轉化的化合物。在某些實施例中,經取代係指具有置換同一碳原子上之兩個氫原子之取代基的部分,諸如用側氧基、亞胺基或硫酮基取代單個碳上之兩個氫原子。如本文所用,術語「經取代」預期包括有機化合物之所有可容許取代基。在一廣泛態樣中,可容許取代基包括有機化合物之非環狀及環狀、分支鏈及非分支鏈、碳環及雜環、芳族及非芳族取代基。對於適當有機化合物,可容許取代基可為一或多個且相同或不同。 The term "substituted" refers to a moiety of a compound having a substituent replacing a hydrogen on one or more carbons or a substitutable heteroatom (eg, NH or NH2 ). It is understood that "substituted" or "substituted" includes the implicit proviso that such substitution is consistent with the permissible valencies of the substituted atom and substituent and that the substitution results in a stable compound, that is, that does not proceed spontaneously, such as by rearrangement. Compounds transformed by , cyclization, elimination, etc. In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with a pendant oxy, imine, or thione group. . As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For appropriate organic compounds, permissible substituents may be one or more and the same or different.
在一些實施例中,取代基可包括任何本文所描述之取代基,例如:鹵素、羥基、側氧基(=O)、硫酮基(=S)、氰基(-CN)、硝基(-NO 2)、亞胺基(=N-H)、肟基(=N-OH)、肼基(=N-NH 2)、-R b-OR a、-R b-OC(O)-R a、-R b-OC(O)-OR a、-R b-OC(O)-N(R a) 2、-R b-N(R a) 2、-R b-C(O)R a、-R b-C(O)OR a、-R b-C(O)N(R a) 2、-R b-O-R c-C(O)N(R a) 2、-R b-N(R a)C(O)OR a、-R b-N(R a)C(O)R a、-R b-N(R a)S(O) tR a(其中t為1或2)、-R b-S(O) tR a(其中t為1或2)、-R b-S(O) tOR a(其中t為1或2)及-R b-S(O) tN(R a) 2(其中t為1或2);及烷基、烯基、炔基、芳基、芳烷基、芳烯基、芳炔基、環烷基、環烷基烷基、雜環烷基、雜環烷基烷基、雜芳基及雜芳烷基,其中之任一者可視情況經烷基、烯基、炔基、鹵素、鹵烷基、鹵烯基、鹵炔基、側氧基(=O)、硫酮基(=S)、氰基(-CN)、硝基(-NO 2)、亞胺基(=N-H)、肟基(=N-OH)、肼(=N-NH 2)、-R b-OR a、-R b-OC(O)-R a、-R b-OC(O)-OR a、-R b-OC(O)-N(R a) 2、-R b-N(R a) 2、-R b-C(O)R a、-R b-C(O)OR a、-R b-C(O)N(R a) 2、-R b-O-R c-C(O)N(R a) 2、-R b-N(R a)C(O)OR a、-R b-N(R a)C(O)R a、-R b-N(R a)S(O) tR a(其中t為1或2)、-R b-S(O) tR a(其中t為1或2)、-R b-S(O) tOR a(其中t為1或2)及-R b-S(O) tN(R a) 2(其中t為1或2)取代;其中各R a獨立地選自氫、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環烷基、雜環烷基烷基、雜芳基或雜芳烷基,其中在價數准許下,各R a可視情況經烷基、烯基、炔基、鹵素、鹵烷基、鹵烯基、鹵炔基、側氧基(=O)、硫酮基(=S)、氰基(-CN)、硝基(-NO 2)、亞胺基(=N-H)、肟基(=N-OH)、肼(=N-NH 2)、-R b-OR a、-R b-OC(O)-R a、-R b-OC(O)-OR a、-R b-OC(O)-N(R a) 2、-R b-N(R a) 2、-R b-C(O)R a、-R b-C(O)OR a、-R b-C(O)N(R a) 2、-R b-O-R c-C(O)N(R a) 2、-R b-N(R a)C(O)OR a、-R b-N(R a)C(O)R a、-R b-N(R a)S(O) tR a(其中t為1或2)、-R b-S(O) tR a(其中t為1或2)、-R b-S(O) tOR a(其中t為1或2)及-R b-S(O) tN(R a) 2(其中t為1或2)取代;且其中各R b獨立地選自直接鍵,或直鏈或分支鏈伸烷基、伸烯基或伸炔基鏈,且各R c為直鏈或分支鏈伸烷基、伸烯基或伸炔基鏈。 In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, pendant oxygen (=O), thione (=S), cyano (-CN), nitro ( -NO 2 ), imino group (=NH), oxime group (=N-OH), hydrazine group (=N-NH 2 ), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N (R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2 ), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a ) 2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl , heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroaralkyl, any of which may be optionally modified by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, halo Alkynyl group, side oxygen group (=O), thione group (=S), cyano group (-CN), nitro group (-NO 2 ), imine group (=NH), oxime group (=N-OH) , hydrazine (=N-NH 2 ), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)- N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N( R a ) 2 , -R b -OR c -C(O)N(R a ) 2 , -R b -N(R a )C(O)OR a , -R b -N(R a )C( O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a ) 2 (where t is 1 or 2) substitution; where each R a is independent is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaralkyl, where in the valence With permission, each R a may be modified by an alkyl group, an alkenyl group, an alkynyl group, a halogen group, a haloalkyl group, a haloalkenyl group, a haloalkynyl group, a pendant oxy group (=O), a thione group (=S), or a cyano group. (-CN), nitro group (-NO 2 ), imino group (=NH), oxime group (=N-OH), hydrazine (=N-NH 2 ), -R b -OR a , -R b - OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -OR c -C(O)N(R a ) 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and - R b -S(O) t N(R a ) 2 (where t is 1 or 2) substituted; and wherein each R b is independently selected from direct bond, or linear or branched chain alkylene, alkenylene or Alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.
與氧原子之雙鍵(諸如側氧基)在本文中表示為「=O」及「(O)」兩者。與氮原子之雙鍵表示為「=NR」及「(NR)」兩者。與硫原子之雙鍵表示為「=S」及「(S)」兩者。Double bonds to oxygen atoms (such as pendant oxygen groups) are represented herein as both "=O" and "(O)". Double bonds with nitrogen atoms are represented by both "=NR" and "(NR)". The double bond with the sulfur atom is represented by both "=S" and "(S)".
如本文所用,片語「非經腸投與(parenteral administration/administered parenterally)」意謂除經腸及局部投與之外的投與模式,通常藉由注射,且包括但不限於靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊椎內及胸骨內注射及輸注。As used herein, the phrase "parenteral administration/administered parenterally" means modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular Intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
片語「醫藥學上可接受」在本文中用於指彼等化合物、材料、組合物及/或劑型在合理醫學判斷之範疇內,適用於接觸人類及動物之組織而無過度毒性、刺激、過敏反應或其他問題或併發症,與合理的益處/風險比相稱。The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and/or dosage forms that are suitable for contact with human and animal tissue without undue toxicity, irritation, Anaphylaxis or other problems or complications, commensurate with a reasonable benefit/risk ratio.
如本文所用,片語「醫藥學上可接受之賦形劑」或「醫藥學上可接受之載劑」意謂醫藥學上可接受之材料、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封材料。各載劑在與調配物之其他成分相容且對患者無害的意義上必須為「可接受」的。可充當醫藥學上可接受之載劑之材料之一些實例包括:(1)糖,諸如乳糖、葡萄糖及蔗糖;(2)澱粉,諸如玉米澱粉及馬鈴薯澱粉;(3)纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)粉末狀黃蓍膠;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,諸如可可脂及栓劑蠟;(9)油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,諸如丙二醇;(11)多元醇,諸如甘油、山梨糖醇、甘露醇及聚乙二醇;(12)酯,諸如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,諸如氫氧化鎂及氫氧化鋁;(15)褐藻酸;(16)無熱原水;(17)等張鹽水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸鹽緩衝液;及(21)醫藥調配物中採用之其他無毒相容性物質。As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler , diluents, excipients, solvents or encapsulating materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, Such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, Sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) ) Alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) pharmaceutical preparations Other non-toxic compatible substances used in the product.
術語「鹽」或「醫藥學上可接受之鹽」係指衍生自此項技術中熟知的多種有機及無機相對離子之鹽。醫藥學上可接受之酸加成鹽可由無機酸及有機酸形成。可衍生鹽的無機酸包含例如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似者。可衍生鹽之有機酸包括例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、順丁烯二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、杏仁酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸及其類似者。醫藥學上可接受之鹼加成鹽可由無機鹼及有機鹼形成。可衍生鹽之無機鹼包括例如鈉、鉀、鋰、銨、鈣、鎂、鐵、鋅、銅、錳、鋁及其類似者。可衍生鹽之有機鹼包括例如一級胺、二級胺及三級胺、經取代之胺(包括天然存在的經取代之胺)、環胺、鹼性離子交換樹脂及其類似者,特定言之,諸如異丙胺、三甲胺、二乙胺、三乙胺、三丙胺及乙醇胺。在一些實施例中,醫藥學上可接受之鹼加成鹽選自銨鹽、鉀鹽、鈉鹽、鈣鹽及鎂鹽。 VI. 實例實例1:目標寡核苷酸中與病症風險增加或降低相關之變體之鑑別 The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable base addition salts can be formed from inorganic bases and organic bases. Inorganic bases from which salts may be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Organic bases from which salts may be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and the like, in particular , such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium salt, potassium salt, sodium salt, calcium salt and magnesium salt. VI. Examples Example 1: Identification of variants in target oligonucleotides associated with increased or decreased risk of disease
大致30,000,000個輸入變體欲在~375,000名來自Biobank組之個體中分析與肝病(諸如非酒精性脂肪性肝炎)之相關性。Approximately 30,000,000 input variants were analyzed for association with liver disease (such as non-alcoholic steatohepatitis) in ~375,000 individuals from the Biobank cohort.
各種目標基因之特定等位基因變體與肝病之間觀測到保護性或不適應相關性。該等相關性將表明,在一些情況下,由目標基因中之任一者編碼之目標蛋白之治療性抑制或調節可為一種治療肝病中之任一者的有效遺傳學方法。 實例2:為了鑑別下調目標mRNA之表現之治療性siRNA之序列的生物資訊選擇Protective or maladaptive associations were observed between specific allelic variants of various target genes and liver disease. These correlations would suggest that, in some cases, therapeutic inhibition or modulation of a protein of interest encoded by any of the genes of interest may be an effective genetic approach to treating any of the liver diseases. Example 2: Bioinformatics selection of sequences for identifying therapeutic siRNA that down-regulates target mRNA
篩選集待基於生物資訊學分析定義。治療性siRNA設計成結合人類目標mRNA,及至少一種毒理學相關物種(諸如非人類靈長類動物(NHP)物種(例如恆河猴或石蟹獼猴))之目標mRNA序列。設計篩選集之驅動器預計為siRNA針對相關物種之總轉錄本的特異性以及物種之間的交叉反應性。測定人類、恆河猴、石蟹獼猴、小鼠及大鼠中針對有義(S)及反義(AS)股之預計特異性。此等指定為「特異性評分」,其考慮藉由siRNA股之完全或部分互補(位置2-18內至多4個錯配)對任何其他轉錄本之非預期下調的可能性,以及錯配的數目及位置。因此,鑑別各siRNA之反義股及有義股之脫靶。另外,潛在脫靶之數目用作特異性評分中之額外特異性因素。如所鑑別,具有高特異性及較低的預計脫靶數之siRNA提供增加之靶向特異性的益處。Screening sets are to be defined based on bioinformatics analysis. Therapeutic siRNA is designed to bind to a human target mRNA, and a target mRNA sequence of at least one toxicologically relevant species, such as a non-human primate (NHP) species (eg, rhesus monkey or stone crab macaque). Drivers for designing screening sets are expected to be siRNA specificity against total transcripts of related species and cross-reactivity between species. The predicted specificity for sense (S) and antisense (AS) strands was determined in humans, rhesus monkeys, macaques, mice and rats. These designations are "specificity scores" that take into account the likelihood of unintended downregulation of any other transcript by full or partial complementation of the siRNA strand (up to 4 mismatches within positions 2-18), as well as the likelihood of mismatches Number and location. Therefore, off-target antisense and sense strands of each siRNA are identified. Additionally, the number of potential off-targets is used as an additional specificity factor in the specificity score. As identified, siRNAs with high specificity and lower predicted off-target numbers offer the benefit of increased target specificity.
除選擇對目標mRNA具有高序列特異性之siRNA序列以外,分析種子區域內之siRNA序列與已知miRNA之種子區域的相似性。siRNA可經由與mRNA分子之3'-UTR內之互補序列鹼基配對以miRNA樣方式作用。互補性通常涵蓋在miRNA之位置2-7 (種子區域)之5'-鹼基。為了規避siRNA經由功能性miRNA結合位點起作用,避開含有天然miRNA種子區域之siRNA股。來自人類、小鼠、大鼠、恆河猴、狗、兔及豬之miRNA中鑑別出之種子區域被稱為「保守」的。將「特異性評分」與miRNA種子分析組合產生「特異性類別」。此分為類別1-4,其中1具有最高特異性且4具有最低特異性。對siRNA之各股指定特異性類別。In addition to selecting siRNA sequences with high sequence specificity for the target mRNA, the siRNA sequences in the seed region are analyzed for similarity with the seed regions of known miRNAs. siRNA can act in a miRNA-like manner by base pairing with complementary sequences within the 3'-UTR of the mRNA molecule. Complementarity usually covers the 5'-bases at positions 2-7 (seed region) of the miRNA. To avoid siRNA acting via functional miRNA binding sites, avoid siRNA strands containing the native miRNA seed region. The seed regions identified in miRNAs from humans, mice, rats, rhesus monkeys, dogs, rabbits and pigs are said to be "conserved". Combining the "Specificity Score" with the miRNA seed analysis produces "Specificity Categories". This is divided into categories 1-4, with 1 having the highest specificity and 4 having the lowest specificity. Each strand of siRNA is assigned a specific class.
評定人類、石蟹獼猴、恆河猴、小鼠及大鼠之物種交叉反應性。該分析係基於使用19個鹼基及17個鹼基之典型siRNA設計(不考慮位置1及19)用於交叉反應性。包括完全匹配以及單一錯配分析。Assess species cross-reactivity in humans, macaques, rhesus monkeys, mice and rats. This analysis is based on a typical siRNA design using 19 bases and 17 bases (disregarding positions 1 and 19) for cross-reactivity. Includes exact match as well as single mismatch analysis.
亦進行用於鑑別具有已知SNP之siRNA靶向區之人類單核苷酸多型性(Single Nucleotide Polymorphism;SNP)資料庫之分析(NCBI-DB-SNP),以鑑別在個體中可為非功能性之含有SNP的siRNA。在此分析中獲得關於SNP在目標序列內位置的資訊以及在病例資料中之次要等位基因頻率(minor allele frequency;MAF)。An analysis of the human Single Nucleotide Polymorphism (SNP) database (NCBI-DB-SNP) for identifying siRNA target regions with known SNPs was also performed to identify possible non-specific mutations in individuals. Functional SNP-containing siRNA. In this analysis, information is obtained about the position of the SNP within the target sequence and the minor allele frequency (MAF) in the case data.
以上方法可用於鑑別下調目標mRNA表現之治療性siRNA。生物資訊學方法亦可用於鑑別結合且下調目標mRNA表現之ASO。 實例3:化學修飾之siRNA The above method can be used to identify therapeutic siRNA that downregulates the expression of target mRNA. Bioinformatics methods can also be used to identify ASOs that bind and downregulate target mRNA expression. Example 3: Chemically modified siRNA
可合成結合目標mRNA之具有化學修飾之siRNA,其中有義股具有諸如修飾模式1S之修飾,且反義股具有諸如修飾模式1AS之修飾。另外,腺苷可置於有義股中之位置19,且尿苷可置於反義股中之位置1。Chemically modified siRNAs can be synthesized that bind target mRNA, where the sense strand has modifications such as modification pattern 1S and the antisense strand has modifications such as modification pattern 1AS. Additionally, adenosine can be placed at position 19 in the sense strand, and uridine can be placed at position 1 in the antisense strand.
亦可合成結合目標mRNA之具有化學修飾之siRNA,其中有義股具有修飾模式2S且反義股具有修飾模式3AS。另外,腺苷可置於有義股中之位置19,且尿苷可置於反義股中之位置1。It is also possible to synthesize chemically modified siRNA that binds target mRNA, in which the sense strand has a modification pattern of 2S and the antisense strand has a modification pattern of 3AS. Additionally, adenosine can be placed at position 19 in the sense strand, and uridine can be placed at position 1 in the antisense strand.
亦可合成結合目標mRNA之具有化學修飾之siRNA,其中有義股具有修飾模式2S且反義股具有修飾模式9AS。另外,腺苷可置於有義股中之位置19,且尿苷可置於反義股中之位置1。It is also possible to synthesize chemically modified siRNA that binds target mRNA, in which the sense strand has a modification pattern of 2S and the antisense strand has a modification pattern of 9AS. Additionally, adenosine can be placed at position 19 in the sense strand, and uridine can be placed at position 1 in the antisense strand.
亦可合成結合目標mRNA之具有化學修飾之siRNA,其中有義股具有修飾模式3S且反義股具有修飾模式3AS。另外,腺苷可置於有義股中之位置19,且尿苷可置於反義股中之位置1。It is also possible to synthesize chemically modified siRNA that binds target mRNA, in which the sense strand has a modification pattern of 3S and the antisense strand has a modification pattern of 3AS. Additionally, adenosine can be placed at position 19 in the sense strand, and uridine can be placed at position 1 in the antisense strand.
亦可合成結合目標mRNA之具有化學修飾之siRNA,其中有義股具有以下中之任一者:所有嘌呤包含2'氟基修飾之嘌呤,且所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶的混合物;所有嘌呤包含2'-O-甲基修飾之嘌呤,且所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶的混合物;所有嘌呤包含2'氟基修飾之嘌呤,且所有嘧啶包含2'-O-甲基修飾之嘧啶;所有嘧啶包含2'氟基修飾之嘧啶,且所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤的混合物;所有嘧啶包含2'-O-甲基修飾之嘧啶,且所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤的混合物;或所有嘧啶包含2'氟基修飾之嘧啶,且所有嘌呤包含2'-O-甲基修飾之嘌呤;且進一步其中反義股具有以下中之任一者:所有嘌呤包含2'氟基修飾之嘌呤,且所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶的混合物;所有嘌呤包含2'-O-甲基修飾之嘌呤,且所有嘧啶包含2'氟基及2'-O-甲基修飾之嘧啶的混合物;所有嘌呤包含2'-O-甲基修飾之嘌呤,且所有嘧啶包含2'氟基修飾之嘧啶;所有嘧啶包含2'氟基修飾之嘧啶,且所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤的混合物;所有嘧啶包含2'-O-甲基修飾之嘧啶,且所有嘌呤包含2'氟基及2'-O-甲基修飾之嘌呤的混合物;或所有嘧啶包含2'-O-甲基修飾之嘧啶,且所有嘌呤包含2'氟基修飾之嘌呤。 實例4:篩選siRNA在培養細胞中之活性It is also possible to synthesize chemically modified siRNA that binds target mRNA, in which the sense strand has any of the following: all purines contain 2' fluoro-modified purines, and all pyrimidines contain 2' fluoro and 2'-O- Mixture of methyl-modified pyrimidines; all purines contain 2'-O-methyl-modified purines, and all pyrimidines contain a mixture of 2'-fluoro and 2'-O-methyl-modified pyrimidines; all purines contain 2'-fluorine All pyrimidines contain 2'-O-methyl-modified purines, and all pyrimidines contain 2'-O-methyl-modified pyrimidines; all pyrimidines contain 2'-fluoro-modified pyrimidines, and all purines contain 2'-fluoro and 2'-O-methyl-modified purines A mixture of all pyrimidines containing 2'-O-methyl modified pyrimidines and all purines containing 2' fluoro and 2'-O-methyl modified purines; or a mixture of all pyrimidines containing 2' fluoro modified pyrimidines , and all purines include 2'-O-methyl modified purines; and further wherein the antisense strand has any of the following: all purines include 2' fluoro modified purines, and all pyrimidines include 2' fluoro and A mixture of 2'-O-methyl modified pyrimidines; all purines containing 2'-O-methyl modified purines, and all pyrimidines containing a mixture of 2'fluoro and 2'-O-methyl modified pyrimidines; all Purines contain 2'-O-methyl modified purines, and all pyrimidines contain 2' fluoro-modified pyrimidines; all pyrimidines contain 2' fluoro-modified pyrimidines, and all purines contain 2' fluoro and 2'-O- A mixture of methyl-modified purines; a mixture of all pyrimidines containing 2'-O-methyl-modified pyrimidines and all purines containing 2'-fluoro and 2'-O-methyl-modified purines; or a mixture of all pyrimidines containing 2' -O-methyl modified pyrimidines, and all purines contain 2' fluoro modified purines. Example 4: Screening siRNA activity in cultured cells
將分析衍生自前述實例中之序列之化學修飾之siRNA在培養細胞中的目標mRNA基因敲減活性。將表現目標mRNA之細胞株以10,000個細胞/孔之細胞密度接種於96孔組織培養盤中之補充有10%胎牛血清的DMEM中,且在水套加濕培育箱中在37℃下在由空氣加5%二氧化碳構成之氛圍中培育過夜。每孔使用0.3 µL脂染胺RNAiMax (Fisher),將siRNA分別轉染至重複兩個孔中之細胞中,最終濃度為10 nM。緘默子選擇陰性對照#1 (ThermoFisher,目錄號4390843)及陽性對照siRNA以10 nM最終濃度轉染,作為對照。在37℃下培育48小時之後,自各孔收穫總RNA,且根據製造商說明書使用TaqMan® Fast Advanced Cells-to-CT™套組(ThermoFisher,目錄號A35374)製備cDNA。在Applied Biosystems 7500快速即時PCR機器上,使用針對人類目標mRNA之TaqMan基因表現分析,藉由即時qPCR量測各孔中目標mRNA之含量,重複三次。使用TaqMan基因表現分析(ThermoFisher)來量測PPIA mRNA之含量,且其用於使用△-△Ct法測定各孔中之相對目標mRNA含量。將資料標準化為未處理細胞中之相對目標mRNA含量。Chemically modified siRNAs derived from the sequences in the previous examples will be analyzed for target mRNA gene knockdown activity in cultured cells. The cell lines expressing the target mRNA were seeded in DMEM supplemented with 10% fetal calf serum in a 96-well tissue culture plate at a cell density of 10,000 cells/well, and incubated at 37°C in a water-jacketed humidified incubator. Incubate overnight in an atmosphere composed of air plus 5% carbon dioxide. Using 0.3 µL Lipofectamine RNAiMax (Fisher) per well, siRNA was transfected into cells in duplicate wells with a final concentration of 10 nM. Silencer selection negative control #1 (ThermoFisher, Catalog No. 4390843) and positive control siRNA were transfected at a final concentration of 10 nM as controls. After 48 hours of incubation at 37°C, total RNA was harvested from each well and cDNA was prepared using the TaqMan® Fast Advanced Cells-to-CT™ Kit (ThermoFisher, Cat. No. A35374) according to the manufacturer's instructions. On an Applied Biosystems 7500 fast real-time PCR machine, the TaqMan gene expression assay for human target mRNA was used to measure the content of target mRNA in each well by real-time qPCR, repeated three times. The amount of PPIA mRNA was measured using a TaqMan Gene Expression Assay (ThermoFisher) and used to determine the relative target mRNA content in each well using the Δ-ΔCt method. Data were normalized to relative target mRNA content in untreated cells.
使用如上文所描述之轉染程序,在第二篩選中測試在10 nM下顯示最大程度之目標mRNA基因敲減之siRNA在1 nM濃度下的活性。可使用ASO進行類似實驗。因此,可鑑別最有效地下調目標mRNA之表現之siRNA及ASO。 實例5:寡核苷酸之肝細胞靶向之GalNAc配體siRNAs that showed maximal target mRNA gene knockdown at 10 nM were tested for activity at a concentration of 1 nM in a second screen using the transfection procedure as described above. Similar experiments can be performed using ASO. Therefore, the siRNAs and ASOs that most effectively downregulate the expression of target mRNA can be identified. Example 5: GalNAc ligand targeting hepatocytes using oligonucleotides
在不將本發明限於此等個別方法之情況下,存在至少兩種將多價N-乙醯基半乳胺糖(GalNAc)配體與寡核苷酸連接之一般方法:固相或溶液相結合。GalNAc配體可連接至固相樹脂用於3'結合,或使用GalNAc胺基亞磷酸酯試劑連接在5'端。對於寡核苷酸序列中之其他核苷,GalNAc胺基亞磷酸酯可在固相上偶聯在序列中之任何位置處。用於與5'端寡核苷酸進行GalNAc結合之胺基亞磷酸酯試劑之非限制性實例顯示於
表 1中。
表 1. GalNAc 結合試劑
在0℃下,向化合物1A (500 g,4.76 mol,476 mL)於2-甲基-THF (2.00 L)中之溶液中逐滴添加含CbzCl (406 g,2.38 mol,338 mL)之2-甲基-THF (750 mL)。在N 2氛圍下在25℃下攪拌混合物2小時。TLC (DCM:MeOH = 20:1,PMA)指示CbzCl完全耗盡,且形成一個新的色點(R f= 0.43)。向反應混合物中添加HCl/EtOAc (1 N,180 mL)且攪拌30 min,藉由經由矽藻土過濾移除白色固體,且真空濃縮濾液,得到呈淡黃色油狀之化合物2A (540 g,2.26 mol,47.5%產率)且其未經進一步純化即用於下一步驟中。 1H NMR: δ 7.28 - 7.41 (m, 5 H), 5.55 (br s, 1 H), 5.01 - 5.22 (m, 2 H), 3.63 - 3.80 (m, 2 H), 3.46 - 3.59 (m, 4 H), 3.29 - 3.44 (m, 2 H), 2.83 - 3.02 (m, 1 H)。 用於製備化合物 4A 之 通用程序 To a solution of compound 1A (500 g, 4.76 mol, 476 mL) in 2-methyl-THF (2.00 L) at 0 °C was added dropwise 2 containing CbzCl (406 g, 2.38 mol, 338 mL) -Methyl-THF (750 mL). Stir the mixture at 25 °C for 2 h under N2 atmosphere. TLC (DCM:MeOH = 20:1, PMA) indicated complete depletion of CbzCl and the formation of a new color point (R f = 0.43). HCl/EtOAc (1 N, 180 mL) was added to the reaction mixture and stirred for 30 min, the white solid was removed by filtration through celite, and the filtrate was concentrated in vacuo to obtain compound 2A (540 g, 2.26 mol, 47.5% yield) and it was used in the next step without further purification. 1 H NMR: δ 7.28 - 7.41 (m, 5 H), 5.55 (br s, 1 H), 5.01 - 5.22 (m, 2 H), 3.63 - 3.80 (m, 2 H), 3.46 - 3.59 (m, 4 H), 3.29 - 3.44 (m, 2 H), 2.83 - 3.02 (m, 1 H). General procedure for the preparation of compound 4A
在0℃下,在N 2氛圍下,向化合物3A (1.00 kg,4.64 mol,HCl)於吡啶(5.00 L)中之溶液中逐滴添加乙酸乙醯酯(4.73 kg,46.4 mol,4.34 L)。在N 2氛圍下在25℃攪拌混合物16小時。TLC (DCM:MeOH = 20:1,PMA)指示化合物3A完全耗盡,且形成兩個新的色點(R f= 0.35)。將反應混合物添加至冷水(30.0 L)中且在0℃下攪拌0.5小時,形成白色固體,過濾且乾燥,得到呈白色固體狀之化合物4A (1.55 kg,3.98 mol,85.8%產率)且其未經進一步純化即用於下一步驟中。 1H NMR: δ 7.90 (d, J =9.29 Hz, 1 H), 5.64 (d, J =8.78 Hz, 1 H), 5.26 (d, J =3.01 Hz, 1 H), 5.06 (dd, J =11.29, 3.26 Hz, 1 H), 4.22 (t, J =6.15 Hz, 1 H), 3.95 - 4.16 (m, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 (s, 3 H), 1.90 (s, 3 H), 1.78 (s, 3 H)。 用於製備化合物 5A 之 通用程序 To a solution of compound 3A (1.00 kg, 4.64 mol, HCl) in pyridine (5.00 L) at 0 °C under N2 atmosphere, acetyl acetate (4.73 kg, 46.4 mol, 4.34 L) was added dropwise . The mixture was stirred at 25 °C for 16 h under N2 atmosphere. TLC (DCM:MeOH = 20:1, PMA) indicated complete depletion of compound 3A and the formation of two new color spots (R f = 0.35). The reaction mixture was added to cold water (30.0 L) and stirred at 0°C for 0.5 h. A white solid formed, which was filtered and dried to obtain compound 4A (1.55 kg, 3.98 mol, 85.8% yield) as a white solid and its It was used in the next step without further purification. 1 H NMR: δ 7.90 (d, J = 9.29 Hz, 1 H), 5.64 (d, J = 8.78 Hz, 1 H), 5.26 (d, J = 3.01 Hz, 1 H), 5.06 (dd, J = 11.29, 3.26 Hz, 1 H), 4.22 (t, J = 6.15 Hz, 1 H), 3.95 - 4.16 (m, 3 H), 2.12 (s, 3 H), 2.03 (s, 3 H), 1.99 ( s, 3 H), 1.90 (s, 3 H), 1.78 (s, 3 H). General procedure for the preparation of compound 5A
向化合物4A (300 g,771 mmol)於DCE (1.50 L)中之溶液中添加TMSOTf (257 g,1.16 mol,209 mL),且在60℃下攪拌2小時,且接著在25℃下攪拌1小時。將化合物2A (203 g,848 mmol)溶解於DCE (1.50 L)中,且添加4 Å粉末分子篩(150 g),在N 2氛圍下攪拌30 min。接著,在0℃下將化合物4A於DCE中之溶液逐滴添加至混合物中。在N 2氛圍下在25℃攪拌混合物16小時。TLC (DCM:MeOH = 25:1,PMA)指示化合物4A完全耗盡,且形成新的色點(R f= 0.24)。將反應混合物過濾,且用飽和NaHCO 3(2.00 L)、水(2.00 L)及飽和鹽水(2.00 L)洗滌。有機層經無水Na 2SO 4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物用2-Me-THE/庚烷(5/3,v/v,1.80 L)濕磨2小時,過濾且乾燥,得到呈白色固體狀之化合物5A (225 g,389 mmol,50.3%產率,98.4%純度)。 1H NMR: δ 7.81 (d, J =9.29 Hz, 1 H), 7.20 - 7.42 (m, 6 H), 5.21 (d, J =3.26 Hz, 1 H), 4.92 - 5.05 (m, 3 H), 4.55 (d, J =8.28 Hz, 1 H), 3.98 - 4.07 (m, 3 H), 3.82 - 3.93 (m, 1 H),3.71 - 3.81 (m, 1 H), 3.55 - 3.62 (m, 1 H), 3.43 - 3.53 (m, 2 H), 3.37 - 3.43 (m, 2 H), 3.14 (q, J =5.77 Hz, 2 H), 2.10 (s, 3 H), 1.99 (s, 3 H), 1.89 (s, 3 H), 1.77 (s, 3 H)。 用於製備 NAcegal- 連接子 - 甲苯磺酸鹽之通用程序 To a solution of compound 4A (300 g, 771 mmol) in DCE (1.50 L) was added TMSOTf (257 g, 1.16 mol, 209 mL) and stirred at 60 °C for 2 h and then at 25 °C for 1 hours. Compound 2A (203 g, 848 mmol) was dissolved in DCE (1.50 L), and 4 Å powdered molecular sieve (150 g) was added and stirred under N2 atmosphere for 30 min. Next, a solution of compound 4A in DCE was added dropwise to the mixture at 0°C. The mixture was stirred at 25 °C for 16 h under N2 atmosphere. TLC (DCM:MeOH = 25:1, PMA) indicated complete consumption of compound 4A and the formation of a new color spot (R f = 0.24). The reaction mixture was filtered and washed with saturated NaHCO3 (2.00 L), water (2.00 L) and saturated brine (2.00 L). The organic layer was dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was wet-triturated with 2-Me-THE/heptane (5/3, v/v, 1.80 L) for 2 hours, filtered and dried to obtain compound 5A as a white solid (225 g, 389 mmol, 50.3% yield rate, 98.4% purity). 1 H NMR: δ 7.81 (d, J = 9.29 Hz, 1 H), 7.20 - 7.42 (m, 6 H), 5.21 (d, J = 3.26 Hz, 1 H), 4.92 - 5.05 (m, 3 H) , 4.55 (d, J = 8.28 Hz, 1 H), 3.98 - 4.07 (m, 3 H), 3.82 - 3.93 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.55 - 3.62 (m, 1 H), 3.43 - 3.53 (m, 2 H), 3.37 - 3.43 (m, 2 H), 3.14 (q, J = 5.77 Hz, 2 H), 2.10 (s, 3 H), 1.99 (s, 3 H), 1.89 (s, 3 H), 1.77 (s, 3 H). General Procedure for Preparation of NAcegal- Linker - Tosylate
在N 2氛圍下,向化合物5A (200 g,352 mmol)於THF (1.0 L)中之溶液中添加無水Pd/C (15.0 g,10%純度)及TsOH (60.6 g,352 mmol)。懸浮液經真空脫氣且用H 2吹掃若干次。在H 2(45 psi)氛圍下在25℃下攪拌混合物3小時。TLC (DCM:MeOH = 10:1,PMA)指示化合物5A完全耗盡,且形成一個新的色點(R f= 0.04)。將反應混合物過濾且減壓濃縮(≤ 40℃),得到殘餘物。用無水DCM (500 mL,用4 Å分子篩乾燥過夜(在300℃下乾燥12小時))稀釋且濃縮,得到殘餘物,且運行Karl Fisher (KF)以檢查水含量。用無水DCM (500 mL)稀釋及濃縮重複此3次,得到呈泡沫式白色固體狀之NAcegal-連接子-TMSOTf (205 g,95.8%產率,TsOH鹽)。 1H NMR: δ 7.91 (d, J =9.03 Hz, 1 H), 7.53 - 7.86 (m, 2 H), 7.49 (d, J =8.03 Hz, 2 H), 7.13 (d, J =8.03 Hz, 2 H), 5.22 (d, J =3.26 Hz, 1 H), 4.98 (dd, J =11.29, 3.26 Hz, 1 H), 4.57 (d, J =8.53 Hz, 1 H), 3.99 - 4.05 (m, 3 H), 3.87 - 3.94 (m, 1 H), 3.79 - 3.85 (m, 1 H), 3.51 - 3.62 (m, 5 H), 2.96 (br t, J =5.14 Hz, 2 H), 2.29 (s, 3 H), 2.10 (s, 3 H), 2.00 (s, 3 H), 1.89 (s, 3 H), 1.78 (s, 3 H)。 用於製備 TRIS-PEG2-CBZ 之流程 用於製備化合物 5B 之 通用程序 To a solution of compound 5A (200 g, 352 mmol) in THF (1.0 L) was added anhydrous Pd/C (15.0 g, 10% purity) and TsOH (60.6 g, 352 mmol) under N2 atmosphere. The suspension was degassed under vacuum and purged several times with H2 . The mixture was stirred at 25°C for 3 hours under H2 (45 psi) atmosphere. TLC (DCM:MeOH = 10:1, PMA) indicated complete depletion of compound 5A and the formation of a new color spot (R f = 0.04). The reaction mixture was filtered and concentrated under reduced pressure (≤ 40°C) to obtain a residue. Dilute and concentrate with anhydrous DCM (500 mL, dried over 4 Å molecular sieves overnight (12 h at 300°C)) to give a residue, and run a Karl Fisher (KF) to check water content. Dilution and concentration with anhydrous DCM (500 mL) were repeated three times to obtain NAcegal-linker-TMSOTf (205 g, 95.8% yield, TsOH salt) as a foamy white solid. 1 H NMR: δ 7.91 (d, J = 9.03 Hz, 1 H), 7.53 - 7.86 (m, 2 H), 7.49 (d, J = 8.03 Hz, 2 H), 7.13 (d, J = 8.03 Hz, 2 H), 5.22 (d, J = 3.26 Hz, 1 H), 4.98 (dd, J = 11.29, 3.26 Hz, 1 H), 4.57 (d, J = 8.53 Hz, 1 H), 3.99 - 4.05 (m , 3 H), 3.87 - 3.94 (m, 1 H), 3.79 - 3.85 (m, 1 H), 3.51 - 3.62 (m, 5 H), 2.96 (br t, J = 5.14 Hz, 2 H), 2.29 (s, 3 H), 2.10 (s, 3 H), 2.00 (s, 3 H), 1.89 (s, 3 H), 1.78 (s, 3 H). Process used to prepare TRIS-PEG2-CBZ General procedure for the preparation of compound 5B
向化合物4B (400 g,1.67 mol,1.00 eq)及NaOH (10 M,16.7 mL,0.10 eq)於THF (2.00 L)中之溶液中添加化合物4B_2 (1.07 kg,8.36 mol,1.20 L, 5.00 eq),在30℃下攪拌混合物2小時。LCMS顯示給出所需MS。將五批溶液合併為一批,接著混合物用水(6.00 L)稀釋,用乙酸乙酯(3.00 L×3)萃取,經合併之有機層用鹽水(3.00 L)洗滌,經Na 2SO 4乾燥,過濾且真空濃縮。粗物質藉由管柱層析(SiO 2,石油醚:乙酸乙酯=100:1-10:1,R f=0.5)純化,得到呈淺黃色油狀之化合物5B (2.36 kg,6.43 mol,76.9%產率)。HNMR: δ 7.31-7.36 (m, 5 H), 5.38 (s, 1 H), 5.11-5.16 (m, 2 H), 3.75 (t, J=6.4 Hz), 3.54-3.62 (m, 6 H), 3.39 (d, J=5.2 Hz), 2.61 (t, J=6.0 Hz)。 用於製備 3- 側氧基 -1- 苯基 -2,7,10- 三氧雜 -4- 氮雜十三烷 -13- 酸 ( 下文 化合物 2B) 之通用程序 To a solution of compound 4B (400 g, 1.67 mol, 1.00 eq ) and NaOH (10 M, 16.7 mL, 0.10 eq ) in THF (2.00 L) was added compound 4B_2 (1.07 kg, 8.36 mol, 1.20 L, 5.00 eq) ) and stir the mixture at 30°C for 2 hours. The LCMS display gives the desired MS. Five batches of solutions were combined into one batch, then the mixture was diluted with water (6.00 L), extracted with ethyl acetate (3.00 L×3), the combined organic layer was washed with brine (3.00 L), and dried over Na 2 SO 4 . Filter and concentrate in vacuo. The crude material was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 100:1-10:1, R f =0.5) to obtain compound 5B as a light yellow oil (2.36 kg, 6.43 mol, 76.9% yield). HNMR: δ 7.31-7.36 (m, 5 H), 5.38 (s, 1 H), 5.11-5.16 (m, 2 H), 3.75 (t, J=6.4 Hz), 3.54-3.62 (m, 6 H) , 3.39 (d, J =5.2 Hz), 2.61 (t, J =6.0 Hz). General procedure for the preparation of 3- Pendantoxy -1- phenyl -2,7,10- trioxa -4- azatridecane -13- acid ( Compound 2B below )
向化合物5B (741 g,2.02 mol,1.00 eq)於DCM (2.80 L)中之溶液中添加TFA (1.43 kg,12.5 mol,928 mL,6.22 eq),在25℃下攪拌混合物3小時。LCMS顯示給出所需MS。混合物用DCM (5.00 L)稀釋,用水(3.00 L×3)、鹽水(2.00 L)洗滌,經合併之有機層經Na 2SO 4乾燥,過濾且真空濃縮,得到呈淺黃色油狀之化合物2B (1800g,粗物質)。HNMR: δ 9.46 (s, 5 H), 7.27-7.34 (m, 5 H), 6.50-6.65 (m, 1 H), 5.71 (s, 1 H), 5.10-5.15 (m, 2 H), 3.68-3.70 (m, 14 H), 3.58-3.61 (m, 6 H), 3.39 (s, 2 H), 2.55 (s, 6 H), 2.44 (s, 2 H)。 用於製備化合物 3B 之 通用程序 To a solution of compound 5B (741 g, 2.02 mol, 1.00 eq ) in DCM (2.80 L) was added TFA (1.43 kg, 12.5 mol, 928 mL, 6.22 eq ) and the mixture was stirred at 25 °C for 3 h. The LCMS display gives the desired MS. The mixture was diluted with DCM (5.00 L), washed with water (3.00 L × 3), brine (2.00 L), the combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain compound 2B as a light yellow oil. (1800g, crude material). HNMR: δ 9.46 (s, 5 H), 7.27-7.34 (m, 5 H), 6.50-6.65 (m, 1 H), 5.71 (s, 1 H), 5.10-5.15 (m, 2 H), 3.68 -3.70 (m, 14 H), 3.58-3.61 (m, 6 H), 3.39 (s, 2 H), 2.55 (s, 6 H), 2.44 (s, 2 H). General procedure for the preparation of compound 3B
在0℃下,向化合物2B (375 g,999 mmol,83.0%純度,1.00 eq)於DCM (1.80 L)中之溶液中添加HATU (570 g,1.50 mol,1.50 eq)及DIEA (258 g,2.00 mol,348 mL,2.00 eq),在0℃下攪拌混合物30 min,接著添加化合物1B (606 g,1.20 mol,1.20 eq),在25℃下攪拌混合物1小時。LCMS顯示給出所需MS。將混合物合併為一批,接著混合物用DCM (5.00 L)稀釋,用1 N HCl水溶液(2.00 L×2)洗滌,接著有機層用飽和Na 2CO 3水溶液(2.00 L×2)及鹽水(2.00 L)洗滌,有機層經Na 2SO 4乾燥,過濾且真空濃縮,得到呈黃色油狀之化合物3B (3.88 kg,粗物質)。 用於製備 TRIS-PEG2-CBZ 之通用程序。 To a solution of compound 2B (375 g, 999 mmol, 83.0% purity, 1.00 eq ) in DCM (1.80 L) at 0 °C was added HATU (570 g, 1.50 mol, 1.50 eq ) and DIEA (258 g, 2.00 mol, 348 mL, 2.00 eq ), stir the mixture at 0°C for 30 min, then add compound 1B (606 g, 1.20 mol, 1.20 eq ), and stir the mixture at 25°C for 1 hour. The LCMS display gives the desired MS. The mixture was combined into one batch, then the mixture was diluted with DCM (5.00 L), washed with 1 N aqueous HCl solution (2.00 L×2), and then the organic layer was washed with saturated aqueous Na 2 CO 3 solution (2.00 L×2) and brine (2.00 L), the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain compound 3B (3.88 kg, crude material) as a yellow oil. General procedure for the preparation of TRIS-PEG2-CBZ .
在25℃下攪拌化合物3B (775 g,487 mmol,50.3%純度,1.00 eq)於HCl/二㗁烷(4 M,2.91 L,23.8 eq)中之溶液2小時。LCMS顯示給出所需MS。真空濃縮混合物,得到殘餘物。接著經合併之殘餘物用DCM (5.00 L)稀釋,用2.5 M NaOH水溶液調整至pH=8,且分離。水相再次用DCM (3.00 L)萃取,接著水溶液用1 N HCl水溶液調整至pH=3,接著用DCM (5.00 L×2)萃取,經合併之有機層用鹽水(3.00 L)洗滌,經Na 2SO 4乾燥,過濾且真空濃縮。粗物質藉由管柱層析(SiO 2,DCM:MeOH=0:1-12:1,0.1% HOAc,R f=0.4)純化。殘餘物用DCM (5.00 L)稀釋,用2.5 M NaOH水溶液調整至pH=8,分離,水溶液再次用DCM (3.00 L)萃取,接著水溶液用6 N HCl水溶液調整至pH=3,用DCM:MeOH=10:1 (5.00 L×2)萃取,經合併之有機層用鹽水(2.00 L)洗滌,經Na 2SO 4乾燥,過濾且真空濃縮,得到殘餘物。接著,殘餘物用MeCN (5.00 L)稀釋,真空濃縮,重複此程序兩次以移除水,得到呈淺黃色油狀之TRIS-PEG2-CBZ (1.25 kg,1.91 mol,78.1%產率,95.8%純度)。 1HNMR: 400 MHz, MeOD, δ 7.30-7.35 (5 H), 5.07 (s, 2 H), 3.65-3.70 (m, 16 H), 3.59 (s, 4 H), 3.45 (t, J=5.6 Hz), 2.51 (t, J=6.0 Hz), 2.43 (t, 6.4 Hz)。 用於製備TriNGal-TRIS-Peg2-Phosph 8c之流程 用於製備化合物 3C 之 通用程序 A solution of compound 3B (775 g, 487 mmol, 50.3% purity, 1.00 eq ) in HCl/dioxane (4 M, 2.91 L, 23.8 eq ) was stirred at 25°C for 2 h. The LCMS display gives the desired MS. The mixture was concentrated in vacuo to give a residue. The combined residues were then diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M aqueous NaOH solution, and separated. The aqueous phase was extracted again with DCM (3.00 L), and then the aqueous solution was adjusted to pH=3 with 1 N HCl aqueous solution, and then extracted with DCM (5.00 L×2). The combined organic layers were washed with brine (3.00 L), and washed with Na Dry over 2SO4 , filter and concentrate in vacuo. The crude material was purified by column chromatography (SiO 2 , DCM:MeOH=0:1-12:1, 0.1% HOAc, R f =0.4). The residue was diluted with DCM (5.00 L), adjusted to pH=8 with 2.5 M NaOH aqueous solution, separated, the aqueous solution was extracted again with DCM (3.00 L), then the aqueous solution was adjusted to pH=3 with 6 N HCl aqueous solution, and DCM:MeOH was used. =10:1 (5.00 L×2) extraction, the combined organic layers were washed with brine (2.00 L), dried over Na 2 SO 4 , filtered and concentrated in vacuo to obtain a residue. Next, the residue was diluted with MeCN (5.00 L) and concentrated in vacuo. This procedure was repeated twice to remove water, yielding TRIS-PEG2-CBZ as a light yellow oil (1.25 kg, 1.91 mol, 78.1% yield, 95.8 % purity). 1 HNMR: 400 MHz, MeOD, δ 7.30-7.35 (5 H), 5.07 (s, 2 H), 3.65-3.70 (m, 16 H), 3.59 (s, 4 H), 3.45 (t, J =5.6 Hz), 2.51 (t, J =6.0 Hz), 2.43 (t, 6.4 Hz). Process used to prepare TriNGal-TRIS-Peg2-Phosph 8c General procedure for the preparation of compound 3C
在0℃下,向化合物1C (155 g,245 mmol,1.00 eq)於ACN (1500 mL)中之溶液中添加TBTU (260 g,811 mmol,3.30 eq)、DIEA (209 g,1.62 mol,282 mL,6.60 eq)及化合物2C (492 g,811 mmol,3.30 eq,TsOH),在15℃下攪拌混合物16小時。LCMS顯示給出所需MS。真空濃縮混合物,得到殘餘物,接著混合物用DCM (2000 mL)稀釋,用1 N HCl水溶液(700 mL×2)、接著飽和NaHCO 3水溶液(700 mL×2)洗滌,且真空濃縮。粗物質藉由管柱層析純化,得到呈黃色固體狀之化合物3C (304 g,155 mmol,63.1%產率,96.0%純度)。 用於製備化合物 4C 之 通用程序 To a solution of compound 1C (155 g, 245 mmol, 1.00 eq ) in ACN (1500 mL) was added TBTU (260 g, 811 mmol, 3.30 eq ), DIEA (209 g, 1.62 mol, 282 mL, 6.60 eq ) and compound 2C (492 g, 811 mmol, 3.30 eq , TsOH), and the mixture was stirred at 15°C for 16 hours. The LCMS display gives the desired MS. The mixture was concentrated in vacuo to give a residue, and the mixture was diluted with DCM (2000 mL), washed with 1 N aqueous HCl (700 mL × 2), then saturated aqueous NaHCO 3 (700 mL × 2), and concentrated in vacuo. The crude material was purified by column chromatography to obtain compound 3C as a yellow solid (304 g, 155 mmol, 63.1% yield, 96.0% purity). General procedure for the preparation of compound 4C
向兩批化合物3C (55.0 g,29.2 mmol,1.00 eq)於MeOH (1600 mL)中之溶液中添加Pd/C (6.60 g,19.1 mmol,10.0 %純度)及TFA (3.34 g,29.2 mmol,2.17 mL,1.00 eq),混合物經真空脫氣且用H 2吹掃。在15℃下在H 2(15 psi)下攪拌混合物2小時。LCMS顯示給出所需MS。過濾混合物,且真空濃縮濾液,得到呈白色固體狀之化合物4C (106 g,54.8 mmol,93.7%產率,96.2%純度,TFA)。 用於製備化合物 5C 之 通用程序 兩個批次平行。在0℃下,向EDCI (28.8 g,150 mmol,1.00 eq)於DCM (125 mL)中之溶液中逐滴添加化合物 4a(25.0 g,150 mmol,1.00 eq),接著在0℃下將混合物添加至含化合物 4(25.0 g,150 mmol,1.00 eq)之DCM (125 mL)中,接著在25℃下攪拌混合物1小時。TLC (石油醚:乙酸乙酯= 3:1,R f= 0.45)顯示,反應物耗盡且形成一個新的色點。反應混合物用DCM (100 mL)稀釋,接著用NaHCO 3水溶液(250 mL×1)及鹽水(250 mL)洗滌,經Na 2SO 4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO 2,石油醚:乙酸乙酯= 100:1至3:1)、TLC (SiO 2,石油醚:乙酸乙酯= 3:1)純化,R f= 0.45,接著減壓濃縮,得到殘餘物。獲得呈無色油狀之化合物 5C(57.0 g,176 mmol,58.4%產率,96.9%純度)且確認。 1 HNMR:EW33072-2-P1A, 400 MHz, DMSO δ9.21 (s, 1 H), 7.07-7.09 (m, 2 H), 6.67-6.70 (m, 2 H), 3.02-3.04 (m, 2 H), 2.86-2.90 (m, 2 H) 用於製備化合物 6 之 通用程序 在0℃下,向化合物 3(79.0 g,41.0 mmol,96.4%純度,1.00 eq,TFA)及化合物 6C(14.2 g,43.8 mmol,96.9%純度,1.07 eq)於DCM (800 mL)中之混合物中逐滴添加TEA (16.6 g,164 mmol,22.8 mL,4.00 eq),在15℃下攪拌混合物16小時。LCMS (EW33072-12-P1B,Rt = 0.844 min)顯示偵測到所需質量。反應混合物用DCM (400 mL)稀釋且用NaHCO 3水溶液(400 mL×1)及鹽水(400 mL×1)洗滌,接著混合物用DCM (2.00 L)稀釋且用0.7 M Na 2CO 3(1000 mL×3)及鹽水(800 mL×3)洗滌,經Na 2SO 4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物未經純化即直接用於下一步驟中。獲得呈白色固體狀之化合物 6(80.0 g,粗物質)且經由 1 HNMR確認:EW33072-12-P1A, 400 MHz, MeOD δ7.02 - 7.04 (m, 2 H), 6.68 - 6.70 (m, 2 H), 5.34 - 5.35 (s, 3 H), 5.07 - 5.08 (d, J= 4.00 Hz, 3 H), 4.62 - 4.64 (d, J= 8.00 Hz, 3 H), 3.71 - 4.16 (m, 16 H), 3.31 - 3.70 (m, 44 H), 2.80 - 2.83 (m, 2 H), 2.68 (m, 2 H), 2.46 - 2.47 (m, 10 H), 2.14 (s, 9 H), 2.03 (s, 9 H), 1.94 - 1.95 (d, J= 4.00 Hz, 18 H)。 用於製備 TriGNal-TRIS-Peg2-Phosph 8c 之通用程序 平行合成兩個批次。向化合物 6C(40.0 g,21.1 mmol,1.00 eq)於DCM (600 mL)中之溶液中逐滴添加含四氮唑二異丙銨(3.62 g,21.1 mmol,1.00 eq)及化合物 7c(6.37 g,21.1 mmol,6.71 mL,1.00 eq)之DCM (8.00 mL),在30℃攪拌混合物1小時,接著逐滴添加含化合物 7c(3.18 g,10.6 mmol,3.35 mL,0.50 eq)之DCM (8.00 mL),在30℃攪拌混合物30 min,接著逐滴添加含化合物 7c(3.18 g,10.6 mmol,3.35 mL,0.50 eq)之DCM (8.00 mL),在30℃攪拌混合物1.5小時。LCMS (EW33072-17-P1C1,Rt = 0.921 min)顯示偵測到所需MS+1。LCMS (EW33072-17-P1C2,Rt = 0.919 min)顯示偵測到所需MS+1。將兩個批次合併用於處理。混合物用DCM (1.20 L)稀釋,用飽和NaHCO 3水溶液(1.60 L×2)、含3% DMF之H 2O (1.60 L×2)、H 2O (1.60 L×3)、鹽水(1.60 L)洗滌,經Na 2SO 4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO 2,DCM:MeOH:TEA = 100:3:2)、TLC (SiO 2,DCM:MeOH = 10:1,R f= 0.45)純化,接著減壓濃縮,得到殘餘物。獲得呈白色固體狀之 化合物 8C(76.0 g,34.8 mmol,82.5%產率,96.0%純度),且經由 1 HNMR確認 :EW33072-19-P1C, 400 MHz, MeOD δ7.13-7.15 (d, J= 8.50 Hz, 2 H), 6.95-6.97 (dd, J=8.38, 1.13 Hz, 2 H), 5.34 (d, J=2.88 Hz, 3 H), .09 (dd, J=11.26, 3.38 Hz, 3 H), 4.64 (d, J=8.50 Hz, 3 H), 3.99 - 4.20 (m, 12 H), 3.88 - 3.98 (m, 5 H), 3.66 - 3.83 (m, 20 H), 3.51 - 3.65 (m, 17 H), 3.33 - 3.50 (m, 9 H), 2.87 (t, J=7.63 Hz, 2 H), 2.76 (t, J=5.94 Hz, 2 H), 2.42 - 2.50 (m, 10 H), 2.14 (s, 9 H), 2.03 (s, 9 H), 1.94 - 1.95 (d, J=6.13 Hz, 18 H), 1.24-1.26 (d, J=6.75 Hz, 6 H), 1.18-1.20 (d, J=6.75 Hz, 6 H) 實例7:使用結合GalNAc之siRNA及ASO之活體外肝細胞靶向 To two batches of compound 3C (55.0 g, 29.2 mmol, 1.00 eq ) in MeOH (1600 mL) were added Pd/C (6.60 g, 19.1 mmol, 10.0 % purity) and TFA (3.34 g, 29.2 mmol, 2.17 mL, 1.00 eq ), the mixture was degassed under vacuum and purged with H2 . The mixture was stirred under H2 (15 psi) at 15°C for 2 hours. The LCMS display gives the desired MS. The mixture was filtered, and the filtrate was concentrated in vacuo to afford compound 4C as a white solid (106 g, 54.8 mmol, 93.7% yield, 96.2% purity, TFA). General procedure for the preparation of compound 5C Two batches are run in parallel. To a solution of EDCI (28.8 g, 150 mmol, 1.00 eq) in DCM (125 mL) was added dropwise (25.0 g, 150 mmol, 1.00 eq) at 0 °C, and the mixture was Added to compound 4 (25.0 g, 150 mmol, 1.00 eq) in DCM (125 mL) and the mixture was stirred at 25°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, R f = 0.45) showed that the reactants were consumed and a new color spot formed. The reaction mixture was diluted with DCM (100 mL), then washed with aqueous NaHCO3 (250 mL×1) and brine (250 mL), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 100:1 to 3:1), TLC (SiO 2 , petroleum ether: ethyl acetate = 3:1), R f = 0.45 , then concentrated under reduced pressure to obtain a residue. Compound 5C (57.0 g, 176 mmol, 58.4% yield, 96.9% purity) was obtained as a colorless oil and confirmed. 1 HNMR: EW33072-2-P1A, 400 MHz, DMSO δ 9.21 (s, 1 H), 7.07-7.09 (m, 2 H), 6.67-6.70 (m, 2 H), 3.02-3.04 (m, 2 H) ), 2.86-2.90 (m, 2 H) General procedure for the preparation of compound 6 To a mixture of compound 3 (79.0 g, 41.0 mmol, 96.4% purity, 1.00 eq, TFA) and compound 6C (14.2 g, 43.8 mmol, 96.9% purity, 1.07 eq) in DCM (800 mL) at 0 °C TEA (16.6 g, 164 mmol, 22.8 mL, 4.00 eq) was added dropwise and the mixture was stirred at 15 °C for 16 h. LCMS (EW33072-12-P1B, Rt = 0.844 min) showed that the required mass was detected. The reaction mixture was diluted with DCM (400 mL) and washed with aqueous NaHCO 3 (400 mL × 1) and brine (400 mL × 1), then the mixture was diluted with DCM (2.00 L) and washed with 0.7 M Na 2 CO 3 (1000 mL ×3) and brine (800 mL ×3), washed with Na 2 SO 4 , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was used directly in the next step without purification. Compound 6 was obtained as a white solid (80.0 g, crude material) and confirmed by 1 HNMR : EW33072-12-P1A, 400 MHz, MeOD δ 7.02 - 7.04 (m, 2 H), 6.68 - 6.70 (m, 2 H) ), 5.34 - 5.35 (s, 3 H), 5.07 - 5.08 (d, J = 4.00 Hz, 3 H), 4.62 - 4.64 (d, J = 8.00 Hz, 3 H), 3.71 - 4.16 (m, 16 H ), 3.31 - 3.70 (m, 44 H), 2.80 - 2.83 (m, 2 H), 2.68 (m, 2 H), 2.46 - 2.47 (m, 10 H), 2.14 (s, 9 H), 2.03 ( s, 9 H), 1.94 - 1.95 (d, J = 4.00 Hz, 18 H). General procedure for preparation of TriGNal-TRIS-Peg2-Phosph 8c Two batches were synthesized in parallel. To a solution of compound 6C (40.0 g, 21.1 mmol, 1.00 eq) in DCM (600 mL) was added dropwise diisopropylammonium tetrazole (3.62 g, 21.1 mmol, 1.00 eq) and compound 7c (6.37 g , 21.1 mmol, 6.71 mL, 1.00 eq) in DCM (8.00 mL), the mixture was stirred at 30°C for 1 hour, and then compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) was added dropwise ), stir the mixture at 30°C for 30 min, then add compound 7c (3.18 g, 10.6 mmol, 3.35 mL, 0.50 eq) in DCM (8.00 mL) dropwise, and stir the mixture at 30°C for 1.5 hours. LCMS (EW33072-17-P1C1, Rt = 0.921 min) shows that the required MS+1 is detected. LCMS (EW33072-17-P1C2, Rt = 0.919 min) shows the required MS+1 detected. The two batches were combined for processing. The mixture was diluted with DCM (1.20 L), with saturated aqueous NaHCO 3 (1.60 L × 2), 3% DMF in H 2 O (1.60 L × 2), H 2 O (1.60 L × 3), and brine (1.60 L ), dried over Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , DCM:MeOH:TEA = 100:3:2), TLC (SiO 2 , DCM:MeOH = 10:1, R f = 0.45), and then concentrated under reduced pressure. A residue is obtained. Compound 8C was obtained as a white solid (76.0 g, 34.8 mmol, 82.5% yield, 96.0% purity), and confirmed by 1 HNMR : EW33072-19-P1C, 400 MHz, MeOD δ 7.13-7.15 (d, J = 8.50 Hz, 2 H), 6.95-6.97 (dd, J =8.38, 1.13 Hz, 2 H), 5.34 (d, J =2.88 Hz, 3 H), .09 (dd, J =11.26, 3.38 Hz, 3 H), 4.64 (d, J =8.50 Hz, 3 H), 3.99 - 4.20 (m, 12 H), 3.88 - 3.98 (m, 5 H), 3.66 - 3.83 (m, 20 H), 3.51 - 3.65 ( m, 17 H), 3.33 - 3.50 (m, 9 H), 2.87 (t, J =7.63 Hz, 2 H), 2.76 (t, J =5.94 Hz, 2 H), 2.42 - 2.50 (m, 10 H ), 2.14 (s, 9 H), 2.03 (s, 9 H), 1.94 - 1.95 (d, J =6.13 Hz, 18 H), 1.24-1.26 (d, J =6.75 Hz, 6 H), 1.18- 1.20 (d, J =6.75 Hz, 6 H) Example 7: In vitro hepatocyte targeting using GalNAc-binding siRNA and ASO
在此實驗中,相較於其中肝細胞株用未與GalNAc部分結合之抗GFP siRNA或ASO處理之對照實驗,表現去唾液酸糖蛋白受體及GFP之肝細胞株將用與GalNAc部分結合之抗GFP siRNA或ASO處理。量測GFP mRNA及蛋白質表現,且將用結合GalNAc之siRNA或ASO處理之細胞中GFP mRNA或蛋白質表現的量標準化並與用未結合GalNAc之siRNA或ASO處理之細胞中GFP mRNA或蛋白質表現的量比較。此可允許測定GalNAc部分之肝細胞靶向能力。多個GalNAc部分可與siRNA或ASO結合且進行比較,以查看哪一GalNAc部分引起最佳肝細胞靶向。此等實驗中待測試之GalNAc部分可為本文所描述之GalNAc部分。In this experiment, compared to control experiments in which liver cell lines were treated with anti-GFP siRNA or ASO that did not bind to the GalNAc moiety, liver cell lines expressing asialoglycoprotein receptor and GFP were treated with anti-GFP siRNA or ASO that did not bind to the GalNAc moiety. Anti-GFP siRNA or ASO treatment. Measurement of GFP mRNA and protein expression, and normalizing the amount of GFP mRNA or protein expression in cells treated with siRNA or ASO that binds GalNAc to that in cells treated with siRNA or ASO that does not bind GalNAc compare. This allows determination of the liver cell targeting ability of the GalNAc moiety. Multiple GalNAc moieties can be combined with siRNA or ASO and compared to see which GalNAc moiety results in the best hepatocyte targeting. The GalNAc moiety to be tested in these experiments can be the GalNAc moiety described herein.
可在用結合或未結合GalNAc部分之siRNA或ASO處理之原代肝細胞中進行類似實驗,且可在原代肝細胞中評定除GFP外之目標mRNA或目標蛋白。 實例8:使用結合GalNAc之siRNA及ASO之活體內肝細胞靶向Similar experiments can be performed in primary hepatocytes treated with siRNA or ASO bound or unbound to the GalNAc moiety, and target mRNAs or target proteins other than GFP can be assessed in primary hepatocytes. Example 8: In vivo hepatocyte targeting using GalNAc-binding siRNA and ASO
在此實驗中,靶向目標mRNA之siRNA或ASO將與GalNAc部分結合且向小鼠投與(n = 5隻/組),且與其中向小鼠投與無GalNAc結合之siRNA或ASO的對照實驗比較。在2天後處死小鼠,且將肝臟冷凍,稍後均質化,且測試目標mRNA及蛋白質表現。將用結合GalNAc之siRNA或ASO處理之小鼠之肝臟中目標mRNA或蛋白質表現的量標準化,且與用未結合GalNAc之siRNA或ASO處理之小鼠之肝臟中GFP mRNA或蛋白質表現的量比較。此可允許測定GalNAc部分之肝臟靶向能力。多個GalNAc部分可與siRNA或ASO結合且進行比較,以查看哪一GalNAc部分引起最佳肝臟靶向。此實驗中包括之GalNAc部分可為展現最大程度之肝細胞靶向之彼等者。此等實驗中待測試之GalNAc部分可為本文所描述之GalNAc部分。 實例9:使用結合GalNAc之siRNA及ASO之肝病小鼠模型中目標mRNA之抑制In this experiment, siRNA or ASO targeting the target mRNA will bind to the GalNAc moiety and be administered to mice (n = 5/group), as well as a control in which mice are administered siRNA or ASO without GalNAc binding. Experimental comparison. Mice were sacrificed after 2 days, and the livers were frozen, later homogenized, and tested for target mRNA and protein expression. The amount of target mRNA or protein expression in the livers of mice treated with siRNA or ASO that binds GalNAc is normalized and compared to the amount of GFP mRNA or protein expression in the livers of mice treated with siRNA or ASO that does not bind GalNAc. This may allow determination of the liver targeting ability of the GalNAc moiety. Multiple GalNAc moieties can be combined with siRNA or ASO and compared to see which GalNAc moiety results in the best liver targeting. The GalNAc fractions included in this experiment were those that exhibited the greatest degree of hepatocyte targeting. The GalNAc moiety to be tested in these experiments can be the GalNAc moiety described herein. Example 9: Inhibition of target mRNA in liver disease mouse model using GalNAc-conjugated siRNA and ASO
在此實驗中,肝病(在此情況下,脂肪肝病)鼠類模型將用於評估目標mRNA對siRNA或ASO抑制之影響。目標mRNA可編碼其中過度表現或過度活化在肝病中起病理性作用之任何目標蛋白。在鼠類模型中,脂肪肝病藉由如下來誘導:對小鼠餵食含有21.1重量%脂肪、41重量%蔗糖及1.25重量%膽固醇之西式飲食(Western Diet;WD) (Teklad飲食,TD. 120528),以及高糖溶液(23.1 g/L d-果糖(Sigma-Aldrich,G8270)及18.9 g/L d-葡萄糖(Sigma-Aldrich,F0127))12週。將4週齡C57Bl/6J小鼠餵食西式飲食代替常規食物12週。此實驗中使用之GalNAc部分可為本文所描述之GalNAc部分。 In this experiment, a murine model of liver disease (in this case, fatty liver disease) will be used to evaluate the effect of target mRNA on siRNA or ASO inhibition. The target mRNA may encode any target protein whose overexpression or overactivation plays a pathological role in liver disease. In a murine model, fatty liver disease is induced by feeding mice a Western Diet (WD) containing 21.1 wt% fat, 41 wt% sucrose, and 1.25 wt% cholesterol (Teklad Diet, TD. 120528). , and high sugar solution (23.1 g/L d-fructose (Sigma-Aldrich, G8270) and 18.9 g/L d-glucose (Sigma-Aldrich, F0127)) for 12 weeks. Four-week-old C57Bl/6J mice were fed a Western diet instead of regular chow for 12 weeks. The GalNAc moiety used in this experiment can be the GalNAc moiety described herein.
簡言之,將小鼠分為五個組:組1:用非靶向對照siRNA處理之脂肪肝病組;組2:用非靶向對照ASO處理之脂肪肝病組;組3:用靶向目標mRNA之siRNA處理之脂肪肝病組;組4:用靶向目標mRNA之ASO處理之脂肪肝病組;組5:正常飲食之對照小鼠。各組含有八隻小鼠(4隻雄性,4隻雌性)。組1-4之siRNA及ASO各自包括與siRNA或ASO連接之GalNAc部分。Briefly, mice were divided into five groups: Group 1: Fatty liver disease group treated with non-targeting control siRNA; Group 2: Fatty liver disease group treated with non-targeting control ASO; Group 3: Fatty liver disease group treated with non-targeting control siRNA Fatty liver disease group treated with mRNA siRNA; Group 4: Fatty liver disease group treated with ASO targeting target mRNA; Group 5: Control mice on a normal diet. Each group contained eight mice (4 males, 4 females). The siRNAs and ASOs of Groups 1-4 each include a GalNAc moiety linked to the siRNA or ASO.
在西式飲食之第12週,在第一次處理前,自各群組收集血液樣本。At week 12 of the Western diet, blood samples were collected from each group before the first treatment.
藉由200 µL皮下注射10 µM濃度之再懸浮於PBS中之裸siRNA或ASO來達成siRNA或ASO之投與。在研究第0天,將對組1小鼠皮下注射非靶向對照siRNA,將對組2小鼠皮下注射非靶向對照ASO,將對組3小鼠皮下注射靶向小鼠中之目標mRNA的siRNA1,將對組4小鼠皮下注射靶向小鼠中之目標mRNA的ASO1,及將對組5小鼠皮下注射媒劑。在第14天開始後每隔一週,將對各組之動物如同第0天給藥,總共5次注射。Administration of siRNA or ASO was achieved by subcutaneous injection of 200 µL of naked siRNA or ASO resuspended in PBS at a concentration of 10 µM. On study day 0, mice in group 1 will be injected subcutaneously with non-targeting control siRNA, mice in group 2 will be injected subcutaneously with non-targeting control ASO, and mice in group 3 will be injected subcutaneously with target mRNA in targeting mice. For siRNA1, mice in Group 4 will be injected subcutaneously with ASO1 targeting the target mRNA in mice, and mice in Group 5 will be injected subcutaneously with vehicle. Every other week after the beginning of day 14, the animals in each group will be dosed as on day 0, for a total of 5 injections.
將進行每週一次抽血且分離血清及血漿。使用VITROS 5,1 FS (Ortho Clinical Diagnostics)來量測血清ALT、AST、總膽固醇及三酸甘油酯含量。用超敏小鼠胰島素ELISA套組(Crystal Chem,90080),根據製造商說明書量測非禁食血漿胰島素。用One Touch Ultra (Life Scan)分析非禁食血糖。計算HOMA IR及QUICKI。Blood will be drawn once a week and serum and plasma will be separated. VITROS 5,1 FS (Ortho Clinical Diagnostics) was used to measure serum ALT, AST, total cholesterol and triglyceride levels. Non-fasting plasma insulin was measured using a high-sensitivity mouse insulin ELISA kit (Crystal Chem, 90080) according to the manufacturer's instructions. Analyze non-fasting blood glucose with One Touch Ultra (Life Scan). Calculate HOMA IR and QUICKI.
在12週西式飲食及siRNA/ASO處理結束時,藉由腹膜內注射0.3 ml戊巴比妥鈉(Nembutal) (5 mg/ml)之後進行頸椎脫位術處死小鼠。經由心臟穿刺收集終末抽取的血清,且量測最終血清ALT、AST、總膽固醇及三酸甘油酯含量,以及非禁食血漿胰島素及葡萄糖。移出肝臟且分為三個部分;一個部分置放於RNAlater中用於mRNA分離,一個部分迅速冷凍以用於蛋白質分離,一個部分在福馬林中固定且接著石蠟包埋。At the end of 12 weeks of Western diet and siRNA/ASO treatment, mice were sacrificed by intraperitoneal injection of 0.3 ml of Nembutal (5 mg/ml) followed by cervical dislocation. The final serum was collected via cardiac puncture, and final serum ALT, AST, total cholesterol and triglyceride levels, as well as non-fasting plasma insulin and glucose were measured. The liver was removed and divided into three parts; one part was placed in RNAlater for mRNA isolation, one part was snap frozen for protein isolation, and one part was fixed in formalin and then paraffin embedded.
使用PureLink套組,根據製造商方案(ThermoFisher目錄號12183020),自置於RNAlater溶液中之組織分離mRNA。根據製造商之方案進行反轉錄酶反應。將樣本儲存在-80℃下,直至使用TaqMan基因表現分析(Applied Biosystems FAM-探針,使用BioRad iCycler)進行即時qPCR,重複三次。相較於來自給藥非特異性對照siRNA及ASO之小鼠之肝臟組織中之目標mRNA含量,來自給藥siRNA及ASO之小鼠之肝臟組織中之目標mRNA表現的降低。相較於來自接受非特異性對照siRNA或ASO之小鼠之肝臟組織中之SDF-1的量,來自接受siRNA及ASO之小鼠之肝臟組織中之SDF-1的量存在預期降低。此等結果顯示,siRNA及ASO誘發肝臟組織中目標mRNA及目標蛋白之基因敲減,以及目標mRNA及目標蛋白表現之降低與SDF-1產生之降低相關。Isolate mRNA from tissue in RNAlater solution using the PureLink kit according to the manufacturer's protocol (ThermoFisher Cat. No. 12183020). Reverse transcriptase reaction was performed according to the manufacturer's protocol. Samples were stored at -80°C until real-time qPCR using TaqMan gene expression assay (Applied Biosystems FAM-probes, using BioRad iCycler) in triplicate. Reduction in target mRNA expression in liver tissue from mice dosed with siRNA and ASO compared to target mRNA levels in liver tissue from mice dosed with non-specific control siRNA and ASO. There was an expected decrease in the amount of SDF-1 in liver tissue from mice receiving siRNA and ASO compared to the amount of SDF-1 in liver tissue from mice receiving non-specific control siRNA or ASO. These results show that siRNA and ASO induce gene knockdown of target mRNA and target protein in liver tissue, and the reduction of target mRNA and target protein expression is related to the reduction of SDF-1 production.
福馬林固定、石蠟包埋之肝臟部分用蘇木精及伊紅(H&E)染色用於評定肝臟組織學,用天狼星紅(Sirius Red) (Sigma,365548-5G)/固綠(Fast Green) (Sigma,F258)染色用於評定纖維化,及用過碘酸-希夫(periodic acid-Schiff;PAS)染色用於評定肝醣累積。由專業病理學家根據NASH CRN評分系統13評估NAFLD活動性評分(NAFLD Activity Score;NAS)及纖維化階段。盲態進行組織評分,其中病理學家不瞭解接受之處理。此等結果顯示,siRNA及ASO誘發肝臟組織中目標mRNA及目標蛋白之基因敲減,以及目標mRNA及目標蛋白之表現之降低與NAS及NASH CRN之降低相關。 實例10:肝病小鼠模型之抑制Formalin-fixed, paraffin-embedded liver sections were stained with hematoxylin and eosin (H&E) for evaluation of liver histology, using Sirius Red (Sigma, 365548-5G)/Fast Green ( Sigma, F258) staining was used to assess fibrosis, and periodic acid-Schiff (PAS) staining was used to assess glycogen accumulation. The NAFLD Activity Score (NAS) and fibrosis stage were assessed by professional pathologists according to the NASH CRN scoring system 13 . Tissue scoring was performed blindly, in which the pathologist was unaware of the treatment received. These results show that siRNA and ASO induce gene knockdown of target mRNA and target protein in liver tissue, and the reduction in the expression of target mRNA and target protein is related to the reduction of NAS and NASH CRN. Example 10: Inhibition of liver disease mouse model
在此實驗中,肝病(在此情況下,高三酸甘油酯血症)鼠類模型將用於評估肝臟中表現之目標蛋白之siRNA或ASO抑制相較於抗小鼠目標蛋白抗體的影響。小鼠品系C57Bl/6 Apoetm1Unc小鼠將維持攝入高脂西式飲食(Research Diets,D12492;按卡路里計,60%脂肪)。目標蛋白可為其中過度表現或過度活化在肝病中起病理性作用之任何目標蛋白。此實驗中使用之GalNAc部分可為本文所描述之GalNAc部分。In this experiment, a murine model of liver disease (in this case, hypertriglyceridemia) will be used to evaluate the impact of siRNA or ASO inhibition of target proteins expressed in the liver compared to anti-mouse target protein antibodies. Mouse strain C57Bl/6 Apoetm1Unc mice will be maintained on a high-fat Western diet (Research Diets, D12492; 60% fat by calories). The target protein may be any target protein in which overexpression or overactivation plays a pathological role in liver disease. The GalNAc moiety used in this experiment can be the GalNAc moiety described herein.
此研究中將使用四組小鼠(n=16隻/組)。動物在研究期間將維持攝入高脂飲食。在第一次注射前第-4天,將移出食物以用於過夜禁食。在第一次注射前第-3天,將所有動物麻醉,且經由頜下靜脈收集300 µL血液於血清分離管中以評定基線三酸甘油酯、血清葡萄糖、胰島素敏感性、總膽固醇含量、HDL膽固醇含量、肝功能以及目標蛋白之血清含量。在研究第0天,將對組1小鼠腹膜內注射600 µL標準生理鹽水,將對組2小鼠腹膜內注射600 µg呈600 µL之抗小鼠目標蛋白抗體,將對組3小鼠皮下注射150 µg於200 µL標準生理鹽水中之靶向編碼小鼠中之目標蛋白之mRNA的GalNAc-siRNA,及將對組4小鼠皮下注射150 µg於200 µL標準生理鹽水中之靶向編碼目標蛋白之mRNA的GalNAc-ASO。在第3天下午,將移出所有組之食物用於過夜禁食。在第4天,將所有組之動物麻醉,且經由頜下靜脈收集150 µL血液於血清分離管中以評定血清三酸甘油酯、葡萄糖、總膽固醇、HDL膽固醇以及目標蛋白之含量。所有組之動物接著將進行口服葡萄糖耐受性測試及胰島素耐受性測試以評估胰島素敏感性。在收集血液及進行胰島素敏感性測試後,將再次如正常一樣供應食物。在第7天開始後,每週一次對組2之動物如同第0天給藥,總共15次注射。在第14天開始後,每隔一週對組3及組4之動物如同第0天給藥,總共8次注射。在第10天開始,每隔一週將對所有組之小鼠禁食(過夜)及抽血(150 µL至血清分離管中),以評定血清三酸甘油酯、葡萄糖、總膽固醇、HDL膽固醇以及目標蛋白之含量,且進行胰島素敏感性測試。在最後一次注射後之第三天,將移出所有組之食物用於過夜禁食。在最後一次注射後第四天,將所有組之動物麻醉,安樂死且經由心臟穿刺抽血以收集500 µL血液至血清分離管中,以評定三酸甘油酯、血清葡萄糖、胰島素敏感性、總膽固醇含量、HDL膽固醇含量、肝功能以及目標蛋白之血清含量。將自所有動物收集來自肝臟、小腸及腸系膜淋巴結之組織,且浸沒於10%中性緩衝福馬林中用於組織病理學分析。亦將自所有動物收集肝臟樣本且置於RNAlater中。將藉由RT-qPCR,使用針對小鼠目標蛋白及小鼠管家基因PPIA之TaqMan分析來評定目標mRNA的含量。Four groups of mice (n=16/group) will be used in this study. Animals will be maintained on a high-fat diet for the duration of the study. On Day -4 before the first injection, food will be removed for overnight fasting. On day -3 before the first injection, all animals were anesthetized, and 300 µL of blood was collected via the submandibular vein in serum separator tubes to assess baseline triglycerides, serum glucose, insulin sensitivity, total cholesterol content, and HDL Cholesterol levels, liver function, and serum levels of target proteins. On day 0 of the study, mice in group 1 were intraperitoneally injected with 600 µL of standard saline, mice in group 2 were intraperitoneally injected with 600 µg of 600 µL anti-mouse target protein antibody, and mice in group 3 were injected subcutaneously. Inject 150 µg of GalNAc-siRNA targeting the mRNA encoding the protein of interest in mice in 200 µL of standard saline, and mice in Group 4 were injected subcutaneously with 150 µg of the encoding target in 200 µL of standard saline. GalNAc-ASO of protein-mRNA. In the afternoon of Day 3, all groups of food will be removed for overnight fasting. On day 4, animals in all groups were anesthetized, and 150 µL of blood was collected via the submandibular vein in serum separator tubes to assess serum triglycerides, glucose, total cholesterol, HDL cholesterol, and target protein levels. Animals in all groups will then undergo oral glucose tolerance testing and insulin tolerance testing to assess insulin sensitivity. After blood collection and insulin sensitivity testing, food will be served as normal again. Starting on day 7, animals in group 2 were dosed once a week as on day 0, for a total of 15 injections. After the beginning of the 14th day, animals in groups 3 and 4 were administered every other week as on day 0, for a total of 8 injections. Beginning on day 10, mice in all groups were fasted (overnight) and blood was drawn (150 µL into serum separator tubes) every other week to assess serum triglycerides, glucose, total cholesterol, HDL cholesterol, and The target protein content and insulin sensitivity testing were performed. On the third day after the last injection, food from all groups will be removed for overnight fasting. On the fourth day after the last injection, animals in all groups were anesthetized, euthanized, and blood was drawn via cardiac puncture to collect 500 µL of blood into serum separator tubes to assess triglycerides, serum glucose, insulin sensitivity, and total cholesterol. content, HDL cholesterol content, liver function and serum content of target protein. Tissue from liver, small intestine and mesenteric lymph nodes will be collected from all animals and immersed in 10% neutral buffered formalin for histopathological analysis. Liver samples will also be collected from all animals and placed in RNAlater. Target mRNA content will be assessed by RT-qPCR using TaqMan analysis for mouse target proteins and mouse housekeeping gene PPIA.
相較於組1 (鹽水)之小鼠,預期用抗體處理之動物(組2)、用GalNAc-siRNA處理之小鼠(組3)及用GalNAc-ASO處理之小鼠(組4)具有降低的三酸甘油酯、總血清膽固醇、血清葡萄糖以及降低的血清目標蛋白含量,及增加的HDL膽固醇及胰島素敏感性。亦預期組2及組3中之動物在肝臟樣本中具有降低的目標mRNA。 實例11:使用GalNAc-siRNA及GalNAc-ASO之非人類靈長類動物中目標mRNA之抑制Animals treated with the antibody (Group 2), mice treated with GalNAc-siRNA (Group 3), and mice treated with GalNAc-ASO (Group 4) were expected to have reduced triglycerides, total serum cholesterol, serum glucose, and reduced serum target protein levels, and increased HDL cholesterol and insulin sensitivity. Animals in Groups 2 and 3 are also expected to have reduced target mRNA in liver samples. Example 11: Inhibition of target mRNA in non-human primates using GalNAc-siRNA and GalNAc-ASO
在此實驗中,高三酸甘油酯血症NHP模型用於評估肝臟中表現之目標mRNA之siRNA或ASO抑制的影響。目標蛋白可為其中過度表現或過度活化在肝病中起病理性作用之任何目標蛋白。將使用三組石蟹獼猴(n=5隻/組),其在起始研究前置於高脂肪飲食(西式靈長類動物飲食,5S2T)。或者,將使用三組恆河猴(n=5隻/組),其在起始研究前置於高果糖飲食。對動物每兩週給與7次皮下注射鹽水(組1)、GalNAc-siRNA (組2)或GalNAc-ASO (組3)。經修飾之GalNAc-siRNA序列可包括本文所描述之任何修飾模式。此實驗中使用之GalNAc部分可為本文所描述之GalNAc部分。將在基線時及在研究之第4、8及14週時收集用於脂質及血糖量測之血液樣本,且分析脂質含量、血清葡萄糖、胰島素敏感性及目標蛋白。在最後一次血液收集2週後,對各群組之所有動物進行屍體解剖。將自所有動物收集來自肝臟、小腸及腸系膜淋巴結之組織,且浸沒於10%中性緩衝福馬林中用於組織病理學分析。亦將自所有動物收集肝臟樣本且置於RNAlater中。將藉由RT-qPCR,使用針對石蟹獼猴或恆河猴目標蛋白以及石蟹獼猴或恆河猴管家基因PPIA之TaqMan分析來評定目標mRNA之含量。In this experiment, the hypertriglyceridemia NHP model was used to evaluate the effects of siRNA or ASO inhibition of target mRNAs expressed in the liver. The target protein may be any target protein in which overexpression or overactivation plays a pathological role in liver disease. Three groups of stone crab macaques (n=5/group) will be used, which were placed on a high-fat diet (Western primate diet, 5S2T) before starting the study. Alternatively, three groups of rhesus monkeys (n=5/group) placed on a high fructose diet prior to initiating the study will be used. Animals were given 7 subcutaneous injections of saline (Group 1), GalNAc-siRNA (Group 2), or GalNAc-ASO (Group 3) every two weeks. Modified GalNAc-siRNA sequences may include any modification pattern described herein. The GalNAc moiety used in this experiment can be the GalNAc moiety described herein. Blood samples for lipid and blood glucose measurements will be collected at baseline and at weeks 4, 8, and 14 of the study, and analyzed for lipid content, serum glucose, insulin sensitivity, and target proteins. Necropsies were performed on all animals in each group 2 weeks after the last blood collection. Tissue from liver, small intestine and mesenteric lymph nodes will be collected from all animals and immersed in 10% neutral buffered formalin for histopathological analysis. Liver samples will also be collected from all animals and placed in RNAlater. The amount of target mRNA will be assessed by RT-qPCR using a TaqMan assay for the stone crab macaque or rhesus monkey target protein and the stone crab macaque or rhesus monkey housekeeping gene PPIA.
預期相較於組1 (鹽水)之動物,用GalNAc-siRNA處理之動物(組2)及用GalNAc-ASO處理之動物(組3)將顯示降低的三酸甘油酯、總血清膽固醇及血清葡萄糖,以及降低的血清目標蛋白含量,及增加的HDL膽固醇及胰島素敏感性。亦預期,組1及組3中之動物將顯示在肝樣本中降低的目標mRNA。 實例12:使用GalNAc-siRNA及GalNAc-ASO之臨床試驗中目標mRNA之抑制It is expected that animals treated with GalNAc-siRNA (Group 2) and animals treated with GalNAc-ASO (Group 3) will show reduced triglycerides, total serum cholesterol and serum glucose compared to animals in Group 1 (saline) , as well as reduced serum target protein levels, and increased HDL cholesterol and insulin sensitivity. It is also expected that animals in Groups 1 and 3 will show reduced target mRNA in liver samples. Example 12: Inhibition of target mRNA in clinical trials using GalNAc-siRNA and GalNAc-ASO
在此研究中,患有高三酸甘油酯血症之人類個體用於評估肝臟中表現之目標mRNA之siRNA或ASO抑制的影響。目標蛋白可為其中過度表現或過度活化在肝病中起病理性作用之任何目標蛋白。該研究中包括之選擇標準為年齡40-90,BMI ≥ 30,且血清三酸甘油酯≥ 250 mg/dL。研究中將包括三組個體(n=15名/組)。對個體每週給與5次皮下注射鹽水(組1)、GalNAc-siRNA (組2)或GalNAc-ASO (組3)。此等實驗中使用之GalNAc部分可包括本文所描述之GalNAc部分。In this study, human individuals with hypertriglyceridemia were used to evaluate the effects of siRNA or ASO inhibition of target mRNAs expressed in the liver. The target protein may be any target protein in which overexpression or overactivation plays a pathological role in liver disease. Selection criteria for inclusion in the study were age 40-90, BMI ≥ 30, and serum triglycerides ≥ 250 mg/dL. Three groups of individuals will be included in the study (n=15/group). Individuals were given 5 subcutaneous injections per week of saline (Group 1), GalNAc-siRNA (Group 2), or GalNAc-ASO (Group 3). The GalNAc moiety used in these experiments can include the GalNAc moiety described herein.
在培養細胞中或在實驗中顯示高活性之來自選擇集合之siRNA或ASO序列在其他實例中描述。將株基線時及在研究之第3、6及12週時收集用於脂質及血糖量測之血液樣本,且分析脂質含量、血清葡萄糖、胰島素敏感性、目標蛋白以及肝臟及腎功能。siRNA or ASO sequences from selected collections that show high activity in cultured cells or in experiments are described in other examples. Blood samples for lipid and blood glucose measurements were collected at baseline and at weeks 3, 6, and 12 of the study, and lipid content, serum glucose, insulin sensitivity, target proteins, and liver and kidney functions were analyzed.
預期相較於組1 (鹽水)之個體,用GalNAc-siRNA處理之個體(組2)及用GalNAc-ASO處理之個體(組3)將顯示降低的三酸甘油酯、總血清膽固醇及血清葡萄糖,以及降低的血清目標蛋白含量,及增加的HDL膽固醇及胰島素敏感性。 實例 13 :寡核苷酸合成 It is expected that individuals treated with GalNAc-siRNA (Group 2) and those treated with GalNAc-ASO (Group 3) will show reduced triglycerides, total serum cholesterol, and serum glucose compared to individuals in Group 1 (saline) , as well as reduced serum target protein levels, and increased HDL cholesterol and insulin sensitivity. Example 13 : Oligonucleotide synthesis
根據胺基亞磷酸酯技術,在寡核苷酸合成中使用之固相上合成RNAi劑(例如siRNA)。使用K&A寡核苷酸合成器。在由受控孔玻璃(controlled pore glass,CPG;500 Å或600 Å,獲自AM Chemicals, Oceanside, CA, USA)製成之固體載體上進行合成。所有2'-OMe及2'-F胺基亞磷酸酯均係購自Hongene Biotech (Union City, CA, USA)。將所有胺基亞磷酸酯溶解於無水乙腈(100 mM)中,且添加分子篩(3 Å)。使用5-苯甲硫基-1H-四唑(BTT,250 mM於乙腈中)或5-乙基硫基-1H-四唑(ETT,250 mM於乙腈中)作為活化劑溶液。偶聯時間為9-18 min (EmpGalNAc)、6 min (2′OMe及2′F)。為了引入硫代磷酸酯鍵聯,使用3-苯基1,2,4-二噻唑啉-5-酮(POS,獲自PolyOrg, Inc., Leominster, Mass., USA)於無水乙腈中之100 mM溶液。RNAi agents (eg, siRNA) are synthesized on the solid phase used in oligonucleotide synthesis according to aminophosphite technology. Use K&A Oligonucleotide Synthesizer. Synthesis was performed on a solid support made of controlled pore glass (CPG; 500 Å or 600 Å, obtained from AM Chemicals, Oceanside, CA, USA). All 2'-OMe and 2'-F aminophosphites were purchased from Hongene Biotech (Union City, CA, USA). All aminophosphites were dissolved in anhydrous acetonitrile (100 mM) and molecular sieves (3 Å) were added. Use 5-benzylthio-1H-tetrazole (BTT, 250 mM in acetonitrile) or 5-ethylthio-1H-tetrazole (ETT, 250 mM in acetonitrile) as the activator solution. Coupling time is 9-18 min (EmpGalNAc), 6 min (2′OMe and 2′F). To introduce phosphorothioate linkages, 100% of 3-phenyl 1,2,4-dithiazolin-5-one (POS, obtained from PolyOrg, Inc., Leominster, Mass., USA) in anhydrous acetonitrile was used mM solution.
在固相合成之後,乾燥固體載體在30℃下用含40 wt%甲胺之水與28%氫氧化銨溶液(Aldrich)之1:1體積溶液處理兩小時。使溶液蒸發,且固體殘餘物復原於水中且藉由陰離子交換HPLC,使用TKSgel SuperQ-5PW 13u管柱純化。緩衝液A為20 mM Tris、5 mM EDTA,pH 9.0且含有20%乙腈,且緩衝液B與緩衝液A相同,但其中添加有1 M氯化鈉。記錄在260 nm下之UV跡線。將適當溶離份合併,接著使用Sephadex G-25介質去鹽。After solid phase synthesis, the dry solid support was treated with a 1:1 volume solution of 40 wt% methylamine in water and 28% ammonium hydroxide solution (Aldrich) at 30°C for two hours. The solution was evaporated and the solid residue was recovered in water and purified by anion exchange HPLC using a TKSgel SuperQ-5PW 13u column. Buffer A is 20 mM Tris, 5 mM EDTA, pH 9.0 and contains 20% acetonitrile, and Buffer B is the same as Buffer A, but with 1 M sodium chloride added. UV trace recorded at 260 nm. The appropriate fractions were combined and then desalted using Sephadex G-25 media.
將等莫耳量之有義股及反義股組合以製備雙螺旋體。在0.1×PBS (磷酸鹽緩衝鹽水,1×,Gibco)中製備雙螺旋體溶液。使雙螺旋體溶液在95℃下黏著5 min,且緩慢冷卻至室溫。藉由在UV-Vis光譜儀上量測在260 nm下於0.1×PBS中之溶液吸光度來測定雙螺旋體濃度。對於一些實驗,換算因數係利用實驗測定的消光係數計算。 實例14:使用結合GalNAc之siRNA及ASO之活體內肝細胞靶向Equimolar amounts of sense and antisense strands were combined to prepare duplexes. Duplex solutions were prepared in 0.1×PBS (phosphate buffered saline, 1×, Gibco). The double helix solution was allowed to adhere at 95°C for 5 min and slowly cooled to room temperature. The duplex concentration was determined by measuring the absorbance of the solution in 0.1×PBS at 260 nm on a UV-Vis spectrometer. For some experiments, the conversion factor is calculated using experimentally determined extinction coefficients. Example 14: In vivo hepatocyte targeting using GalNAc-binding siRNA and ASO
在此實驗中,靶向目標mRNA之siRNA或ASO將與GalNAc部分結合且向小鼠投與(n = 5隻/組),且與其中向小鼠投與無GalNAc結合之siRNA或ASO的對照實驗比較。在2天後處死小鼠,且將肝臟冷凍,稍後均質化,且測試目標mRNA及蛋白質表現。將用結合GalNAc之siRNA或ASO處理之小鼠之肝臟中目標mRNA或蛋白質表現的量標準化,且與用未結合GalNAc之siRNA或ASO處理之小鼠之肝臟中GFP mRNA或蛋白質表現的量比較。此可允許測定GalNAc部分之肝臟靶向能力。多個GalNAc部分可與siRNA或ASO結合且進行比較,以查看哪一GalNAc部分引起最佳肝臟靶向。GalNAc部分可為在實例6中展現最大程度之肝細胞靶向之彼等者。此等實驗中測試之GalNAc部分可為本文所描述之GalNAc部分,諸如化合物1或化合物2。 實例15:結合GalNAc之siRNA對小鼠中PLIN1之基因敲減In this experiment, siRNA or ASO targeting the target mRNA will bind to the GalNAc moiety and be administered to mice (n = 5/group), as well as a control in which mice are administered siRNA or ASO without GalNAc binding. Experimental comparison. Mice were sacrificed after 2 days, and the livers were frozen, later homogenized, and tested for target mRNA and protein expression. The amount of target mRNA or protein expression in the livers of mice treated with siRNA or ASO that binds GalNAc is normalized and compared to the amount of GFP mRNA or protein expression in the livers of mice treated with siRNA or ASO that does not bind GalNAc. This may allow determination of the liver targeting ability of the GalNAc moiety. Multiple GalNAc moieties can be combined with siRNA or ASO and compared to see which GalNAc moiety results in the best liver targeting. The GalNAc moieties may be those that demonstrated greatest hepatocyte targeting in Example 6. The GalNAc moiety tested in these experiments can be a GalNAc moiety described herein, such as Compound 1 or Compound 2. Example 15: Gene knockdown of PLIN1 in mice using GalNAc-binding siRNA
實例GalNAc部分ETL17與靶向實例目標mRNA之siRNA結合。序列顯示於 表 2中。在該表中,Nf (例如Af、Cf、Gf、Tf或Uf)為2'氟基修飾之核苷,n (例如a、c、g、t或u)為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。測試siRNA在小鼠中之活性。 Example GalNAc moiety ETL17 binds to siRNA targeting example target mRNA. The sequences are shown in Table 2 . In this table, Nf (such as Af, Cf, Gf, Tf or Uf) is a 2' fluoro-modified nucleoside, n (such as a, c, g, t or u) is a 2' O-methyl modified nucleoside nucleoside, and "s" is a phosphorothioate linkage. Test the activity of siRNA in mice.
藉由眶後途徑,在第-14天對六至八週齡雌性小鼠(C57BL/6)注射10 μL重組腺相關病毒8 (AAV8)載體(1.7 × 10E 13個基因體複本/mL)。重組AAV8在封裝於AAV8殼體中之AAV2主鏈中含有在人類甲狀腺素結合球蛋白啟動子控制下的人類PLIN1序列(NM_002666.5) (AAV8-TBG-h-PLIN1)。在第0天,對感染小鼠(n=4)給與皮下注射單次100 μg劑量之結合GalNAc之siRNA或作為媒劑對照之PBS。 Six- to eight-week-old female mice (C57BL/6) were injected with 10 μL of recombinant adeno-associated virus 8 (AAV8) vector (1.7 × 10E 13 genome copies/mL) via the retroorbital route on day -14. Recombinant AAV8 contains the human PLIN1 sequence (NM_002666.5) under the control of the human thyroxine-binding globulin promoter (AAV8-TBG-h-PLIN1) in the AAV2 backbone encapsulated in the AAV8 capsid. On day 0, infected mice (n=4) were given a single 100 μg dose of GalNAc-binding siRNA or PBS as a vehicle control by subcutaneous injection.
在皮下注射後第10天將小鼠安樂死,且自各小鼠收集肝臟樣本並置於RNAlater (ThermoFisher目錄號AM7020)中直至處理。藉由在均質化緩衝液(Maxwell RSC simplyRNA組織套組)中,使用設定為5000 rpm持續兩個10秒循環之Percellys 24組織均質器(Bertin Instruments)均質化肝臟組織來製備總肝臟RNA。在Maxwell RSC 48平台(Promega Corporation)上,根據製造商之建議純化來自溶解物之總RNA。使用Quanta qScript cDNA SuperMix (VWR,目錄號95048-500),根據製造商說明書進行cDNA之製備。在QuantStudio™ 6 Pro 即時PCR系統上,使用針對人類PLIN1 (ThermoFisher,分析號Hs01106925_m1)及小鼠管家基因PPIA (ThermoFisher,分析號Mm02342430_g1)之TaqMan分析及PerfeCTa® qPCR FastMix®, Low ROX™ (VWR,目錄號101419-222),藉由RT-qPCR評定肝臟PLIN1 mRNA之相對含量,重複三次。將資料標準化為接受PBS之動物中之平均PLIN1 mRNA含量。結果顯示於
表 3中。在第10天,相對於接受PBS之小鼠,所有測試之siRNA均引起平均肝臟PLIN1 mRNA之減少。此等資料指示,與GalNAc部分(諸如ETL17)結合之siRNA適用於基因敲減肝臟中之目標mRNA。 表2.實例siRNA序列
ETL17與靶向另一實例目標mRNA之siRNA結合。將siRNA與GalNAc配體ETL17連接,隨後與有義股之5'端之硫代磷酸酯鍵聯連接。siRNA描述於 表 6中。在該表中,Nf (例如Af、Cf、Gf、Tf或Uf)為2'氟基修飾之核苷,dN (例如dA、dC、dG、dT或dU)為2'去氧基修飾之核苷,n (例如a、c、g、t或u)為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。 ETL17 binds to siRNA targeting another example target mRNA. The siRNA was linked to the GalNAc ligand ETL17 and subsequently to the phosphorothioate linkage at the 5' end of the sense strand. siRNAs are described in Table 6 . In this table, Nf (such as Af, Cf, Gf, Tf or Uf) is a 2' fluoro-modified nucleoside, and dN (such as dA, dC, dG, dT or dU) is a 2' deoxy-modified nucleoside Glycoside, n (e.g., a, c, g, t, or u) is a 2'O-methyl modified nucleoside, and "s" is a phosphorothioate linkage.
藉由眶後途徑,對六至八週齡雌性小鼠(C57BL/6)注射5 μL重組腺相關病毒8 (AAV8)載體(2.7 × 10E13個基因體複本/mL)。重組AAV8在封裝於AAV8殼體中之AAV2主鏈中含有在人類甲狀腺素結合球蛋白啟動子控制下之開讀框及人類MST1序列之大部分3'UTR (NM_020998.4) (AAV8-TBG-h-MST1)。在感染後第13天,收集血清,且使用R&D之人類MSP/MST1 DuoSet ELISA (目錄號DY352)來量測各小鼠中人類MSP之含量。按照關於緩衝液及溶液之所有試劑製備之製造商說明書。所有測試樣本使用1:50之血清樣本稀釋液。套組中所包括之重組MSP用於產生10,000 pg/mL至0 pg/mL之標準曲線。使用PerkinElmer Envision多模式盤讀取器,讀取培養盤在450 nm下之光密度。藉由內插法,使用最小平方擬合(Prism版本9,Software MacKiev),根據標準曲線計算各小鼠血清樣本中MSP之濃度。Six- to eight-week-old female mice (C57BL/6) were injected with 5 μL of recombinant adeno-associated virus 8 (AAV8) vector (2.7 × 10E13 genome copies/mL) via the retroorbital route. Recombinant AAV8 contains the open reading frame under the control of the human thyroxine-binding globulin promoter and most of the 3'UTR of the human MST1 sequence (NM_020998.4) in the AAV2 backbone encapsulated in the AAV8 capsid (AAV8-TBG- h-MST1). On day 13 post-infection, serum was collected, and the human MSP content in each mouse was measured using R&D's Human MSP/MST1 DuoSet ELISA (Cat. No. DY352). Follow the manufacturer's instructions for preparation of all reagents of buffers and solutions. All test samples use a 1:50 serum sample dilution. Recombinant MSP included in the kit was used to generate a standard curve from 10,000 pg/mL to 0 pg/mL. Read the optical density of culture plates at 450 nm using a PerkinElmer Envision multi-mode plate reader. By interpolation, the concentration of MSP in each mouse serum sample was calculated based on the standard curve using least squares fitting (Prism version 9, Software MacKiev).
將小鼠分配至各組(n=3)中,以使得各組具有類似的MSP血清含量,且接著給與皮下注射單次60 μg劑量之結合GalNAc之siRNA或作為媒劑對照的PBS。在注射之後第0、4及12天,收集血清以藉由ELISA,使用上文所描述之方法評定血清MSP濃度。在各時間點之MSP血清濃度係相對於各個別小鼠之第0天樣本中MSP之含量得出。結果顯示於 表 4中。此等資料指示,與GalNAc部分(諸如ETL17)結合之siRNA適用於基因敲減肝臟中之額外目標mRNA分泌的蛋白質。 Mice were assigned to groups (n=3) such that groups had similar MSP serum levels and were then given a single 60 μg dose of subcutaneous injection of GalNAc-binding siRNA or PBS as a vehicle control. On days 0, 4 and 12 after injection, sera were collected to assess serum MSP concentrations by ELISA using the method described above. MSP serum concentrations at each time point were relative to the MSP content in the Day 0 sample from each individual mouse. The results are shown in Table 4 . These data indicate that siRNA binding to a GalNAc moiety such as ETL17 is suitable for knockdown of proteins secreted from additional target mRNAs in the liver.
在第12天將小鼠處死,且自各小鼠收集肝臟樣本並置於RNAlater (ThermoFisher目錄號AM7020)中直至處理。藉由在均質化緩衝液(Maxwell RSC simplyRNA組織套組)中,使用設定為5000 rpm持續兩個10秒循環之Percellys 24組織均質器(Bertin Instruments)均質化肝臟組織來製備總肝臟RNA。在Maxwell RSC 48平台(Promega Corporation)上,根據製造商之建議純化來自溶解物之總RNA。使用Quanta qScript cDNA SuperMix (VWR,目錄號95048-500),根據製造商說明書進行cDNA之製備。在QuantStudio™ 6 Pro 即時PCR系統上,使用針對人類MST1 (ThermoFisher,分析號Hs00360684_m1)及小鼠管家基因PPIA (ThermoFisher,分析號Mm02342430_g1)之TaqMan分析,以及PerfeCTa® qPCR FastMix®, Low ROX™ (VWR,目錄號101419-222),藉由RT-qPCR評定肝臟MST1 mRNA的相對含量,重複三次。將資料標準化為接受PBS之動物中的含量。結果顯示於
表 5中。此等資料指示,與GalNAc部分(諸如ETL17)結合之siRNA適用於基因敲減肝臟中之額外目標mRNA。
表4. AAV8-TBG-h-MST1小鼠中之相對平均血清人類MSP含量
研究中使用三組(n=4隻/組)8週齡雄性ICR小鼠(Invigo)。在研究第0天,對組1小鼠皮下注射100 μL無菌PBS,對組2小鼠皮下注射60 μg於100 μL無菌PBS中之siRNA 1811,且對組3小鼠皮下注射200 μg於100 μL無菌PBS中之siRNA 1818。在研究第14天,將所有組之動物麻醉且接著安樂死。自所有動物收集肝臟樣本且置於RNAlater™穩定溶液(Thermo Fisher,目錄號AM7020)中。在設定為5000 rpm,持續兩個10秒循環之Percellys 24組織均質器(Bertin Instruments)中,使用軟組織均質化套組CK14 (Bertin Instruments,目錄號P000933-LYSK0-A)在均質化緩衝液(Maxwell RSC simplyRNA組織套組)中處理肝臟樣本。在Maxwell RSC 48平台(Promega Corporation)上,根據製造商之建議純化來自肝臟溶解物之總RNA。在QuantStudio 6 Pro儀(Applied Biosystems)上,使用針對小鼠基因A及小鼠管家基因PPIA之TaqMan分析,藉由RT-qPCR評定各肝臟樣本中基因A mRNA之相對含量,且接著使用△-△Ct法標準化為對照小鼠(組1)之平均值。Three groups (n=4/group) of 8-week-old male ICR mice (Invigo) were used in the study. On study day 0, mice in group 1 were injected subcutaneously with 100 μL of sterile PBS, mice in group 2 were injected subcutaneously with 60 μg of siRNA 1811 in 100 μL sterile PBS, and mice in group 3 were injected subcutaneously with 200 μg in 100 μL. siRNA 1818 in sterile PBS. On study day 14, animals in all groups were anesthetized and subsequently euthanized. Liver samples were collected from all animals and placed in RNAlater™ stabilizing solution (Thermo Fisher, Cat. No. AM7020). Soft tissue homogenization kit CK14 (Bertin Instruments, catalog number P000933-LYSK0-A) was used in a Percellys 24 tissue homogenizer (Bertin Instruments) set to 5000 rpm for two 10 sec cycles in homogenization buffer (Maxwell Liver samples were processed using the RSC simplyRNA tissue kit. Total RNA from liver lysates was purified on a Maxwell RSC 48 platform (Promega Corporation) according to the manufacturer's recommendations. The relative content of gene A mRNA in each liver sample was assessed by RT-qPCR on a QuantStudio 6 Pro instrument (Applied Biosystems) using TaqMan assays for mouse gene A and mouse housekeeping gene PPIA, and then using Δ-Δ The Ct method was normalized to the mean value of control mice (group 1).
在此實例中,將額外GalNAc部分(ETL1)與ETL17比較。肝臟mRNA分析之結果顯示於
表 7中。相較於注射PBS之小鼠(組1),用靶向ETL1之siRNA (ETD01811,組2)處理之動物之肝臟基因A mRNA含量具有78%相對基因敲減,而用靶向ETL17之siRNA (siRNA 1818,組3)處理之動物具有83%基因敲減。因此,具有本文所描述之GalNAc部分之化合物在基因敲減目標(諸如目標mRNA)方面可優於另一GalNAc部分或至少與其一樣有效。 表7:用靶向基因A之siRNA處理之小鼠中第14天的基因A mRNA肝含量
ETL1顯示於下,其中J指示與寡核苷酸之連接: 。 實例18.測試 MST1siRNA ETD01821、ETD01822、ETD01823及ETD01826在非人類靈長類動物中之活性 ETL1 is shown below, where J indicates attachment to the oligonucleotide: . Example 18. Testing the activity of MST1 siRNA ETD01821, ETD01822, ETD01823 and ETD01826 in non-human primates
此研究使用四組(n=3隻/組)3-6 kg雄性石蟹獼猴(Zhaoqing Chuangyao Biotechnology Co., Ltd及Guangzhou Xianngguan Biotechnology Co., Ltd)。This study used four groups (n=3/group) of 3-6 kg male stone crab macaques (Zhaoqing Chuangyao Biotechnology Co., Ltd and Guangzhou Xianngguan Biotechnology Co., Ltd).
在研究第0天,對組1石蟹獼猴皮下注射單次5 mg/kg劑量(0.2 mL劑量體積/kg體重)之以25 mg/mL之siRNA濃度調配於PBS中的ETD01821,對組2石蟹獼猴注射單次5 mg/kg劑量(0.2 mL劑量體積/kg體重)之以25 mg/mL之siRNA濃度調配於PBS中的ETD01822,對組3石蟹獼猴注射單次5 mg/kg劑量(0.2 mL劑量體積/kg體重)之以25 mg/mL之siRNA濃度調配於PBS中的ETD01823,對組4石蟹獼猴注射單次5 mg/kg劑量(0.2 mL劑量體積/kg體重)之以25 mg/mL之siRNA濃度調配於PBS中的ETD01826,siRNA序列顯示於 表 8中,其中「Nf」為2'氟基修飾之核苷,「n」為2' O-甲基修飾之核苷,且「s」為硫代磷酸酯鍵聯。藉由臨床症狀所量測,該注射一般具有良好耐受性。 On study day 0, stone crab macaques in group 1 were subcutaneously injected with a single dose of 5 mg/kg (0.2 mL dose volume/kg body weight) of ETD01821 formulated at a siRNA concentration of 25 mg/mL in PBS, and stone crab macaques in group 2 A single dose of 5 mg/kg (0.2 mL dose volume/kg body weight) was injected with ETD01822 formulated at a siRNA concentration of 25 mg/mL in PBS. Group 3 stone crab macaques were injected with a single dose of 5 mg/kg (0.2 mL dose). Volume/kg body weight) was formulated with ETD01823 in PBS at a siRNA concentration of 25 mg/mL. Group 4 stone crab macaques were injected with a single dose of 5 mg/kg (0.2 mL dose volume/kg body weight) with 25 mg/mL. The siRNA concentration was prepared in ETD01826 in PBS. The siRNA sequence is shown in Table 8 , where "Nf" is a 2' fluoro-modified nucleoside, "n" is a 2' O-methyl modified nucleoside, and "s" It is a phosphorothioate linkage. The injection was generally well tolerated as measured by clinical symptoms.
在研究持續時間期間,所有石蟹獼猴均不具有異常臨床症狀,除了第101號動物,其在給藥後第65天發現死亡。屍體解剖揭露重度胃穿孔可能為死亡原因。此可在石蟹獼猴中自發地進行。All stone crab macaques had no abnormal clinical symptoms during the duration of the study, except animal No. 101, which was found dead on day 65 post-dose. Autopsy revealed severe gastric perforation as the possible cause of death. This occurs spontaneously in stone crab macaques.
在研究第-8、-1、7、14、21天及第28天,記錄體重。結果顯示於 表 9中。資料指示,組1至4中之動物之體重不會具有有意義的變化。 Body weight was recorded on study days -8, -1, 7, 14, 21 and 28. The results are shown in Table 9 . The data indicate that animals in Groups 1 to 4 will not have meaningful changes in body weight.
在研究第-8、-2、7、14天及第28天,將血液收集至不具有抗凝劑之管中且收集血清。分析臨床化學參數,包含ALT、AST、ALP、TBIL、DBIL、GLU、GGT、TP、TG、CHOL、HDL、LDL、BUN及CREA。當相較於治療前研究第-8天及研究第-2天時,用ETD01821、ETD01822、ETD01823或ETD01926處理之動物在研究第7天開始直至研究第28天,在ALT、AST、ALP、TBIL、DBIL、GLU、GGT、TP、TG、CHOL、HDL、LDL、BUN及CREA方面未顯示有意義的變化。臨床化學之結果指示,所有siRNA一般均具有良好耐受性。結果顯示於 表 10-14中。 On study days -8, -2, 7, 14, and 28, blood was collected into tubes without anticoagulant and serum was collected. Analyze clinical chemistry parameters, including ALT, AST, ALP, TBIL, DBIL, GLU, GGT, TP, TG, CHOL, HDL, LDL, BUN and CREA. When compared to pre-treatment study day -8 and study day -2, animals treated with ETD01821, ETD01822, ETD01823, or ETD01926 had higher levels of ALT, AST, ALP, TBIL starting on study day 7 through study day 28 , DBIL, GLU, GGT, TP, TG, CHOL, HDL, LDL, BUN and CREA did not show meaningful changes. Clinical chemistry results indicated that all siRNAs were generally well tolerated. The results are shown in Tables 10-14 .
在研究第-8、-2、7、14天及第28天,將約1 mL之全血收集至具有EDTA-K2作為抗凝劑之管中。分析血液學參數,包括WBC、NEUT、LYMP、MONO、EOS、BASO、RBC、HGB、HCT、MCV、MCH、MCHC、RDW、PLT、MPV、PCT及PDW。當相較於治療前研究第-8天及研究第-2天時,用ETD01821、ETD01822、ETD01823或ETD01926處理之動物在研究第7天開始直至研究第28天,在此等血液參數方面未顯示有意義的變化。血液學分析之結果指示,所有siRNA一般均具有良好耐受性。結果顯示於 表 15-19中。 On study days -8, -2, 7, 14, and 28, approximately 1 mL of whole blood was collected into tubes with EDTA-K2 as anticoagulant. Analyze hematology parameters including WBC, NEUT, LYMP, MONO, EOS, BASO, RBC, HGB, HCT, MCV, MCH, MCHC, RDW, PLT, MPV, PCT and PDW. When compared to pre-treatment study day -8 and study day -2, animals treated with ETD01821, ETD01822, ETD01823, or ETD01926 did not show significant differences in these hematological parameters beginning on study day 7 through study day 28 Meaningful change. Results from hematological analyzes indicated that all siRNAs were generally well tolerated. The results are shown in Tables 15-19 .
在研究第-8、-2、7、14、28、42、56、70、77、84、91、98天及第105天,將血液收集至不具有抗凝劑之管中且收集血清用於測定血清巨噬細胞刺激蛋白(macrophage stimulating protein;MSP)含量。在稍後時間點,即在第42、56、70、77、84、91、98天及第105天,獲取額外血清樣本。使用定製AlphaLISA分析(PerkinElmer)評估猴血清樣本中之個別巨噬細胞刺激蛋白(MSP)濃度。簡言之,將5 μL以1:50稀釋於1× AlphaLISA HiBlock中之血清樣本置於96孔盤之孔中,隨後添加5 μL 4×抗MSP受體珠粒溶液。在室溫下培育30分鐘之後,添加5 μL 4×生物素化抗MSP抗體溶液,且在室溫下培育培養盤60分鐘。接下來,添加5 μL 4×鏈球菌親生物素蛋白供體珠粒溶液,且在室溫下另外培育培養盤30分鐘。在Envision 2105多模式讀盤器(PerkinElmer)上分析培養盤。使用重組人類MSP (R&D Systems)生成標準曲線。在各時間點各個體之MSP血清濃度係相對於彼個體在第-2天及第-8天之MSP血清濃度平均值得出。群組平均值之結果顯示於 表 20中,且個別值顯示於 表 21中。在用測試品處理後,在第7天開始,所有動物中之MSP血清含量均降低,且至少直至第28天仍降低。用ETD01821處理之猴之血清MSP含量相對於給藥前含量具有最大降低,顯示相較於給藥前含量,直至第105天降低的平均血清MSP含量。 On study days -8, -2, 7, 14, 28, 42, 56, 70, 77, 84, 91, 98, and 105, blood was collected into tubes without anticoagulant and serum collected for To measure the serum macrophage stimulating protein (MSP) content. Additional serum samples were obtained at later time points, namely on days 42, 56, 70, 77, 84, 91, 98 and 105. Individual macrophage stimulating protein (MSP) concentrations in monkey serum samples were assessed using a custom AlphaLISA assay (PerkinElmer). Briefly, 5 μL of serum sample diluted 1:50 in 1× AlphaLISA HiBlock was placed into the wells of a 96-well plate, followed by the addition of 5 μL of 4× anti-MSP receptor bead solution. After incubation for 30 minutes at room temperature, 5 μL of 4×biotinylated anti-MSP antibody solution was added and the plate was incubated at room temperature for 60 minutes. Next, 5 μL of 4× streptavidin donor bead solution was added and the plate was incubated for an additional 30 minutes at room temperature. Culture plates were analyzed on an Envision 2105 multimode plate reader (PerkinElmer). Standard curves were generated using recombinant human MSP (R&D Systems). The MSP serum concentration for each individual at each time point was calculated relative to the average of that individual's MSP serum concentration on Day -2 and Day -8. The results for the group average are shown in Table 20 and the individual values are shown in Table 21 . After treatment with the test article, MSP serum levels were reduced in all animals starting on day 7 and remained reduced at least until day 28. Monkeys treated with ETD01821 had the greatest reduction in serum MSP levels relative to pre-dose levels, showing a decrease in mean serum MSP levels up to day 105 compared to pre-dose levels.
在研究第-8天及第28天,用舒泰(Zoletil) (1.5-5.0 mg/kg,i.m.)及甲苯噻𠯤(xylazine) (0.5-2.0 mg/kg,i.m.)將動物麻醉,且收集3-4 mg肝臟活檢體。接著將活檢體置於10 v/v RNAlater中20秒且儲存在4℃下24小時,接著移除RNAlater™ 穩定溶液(Thermo Fisher,目錄號AM7020),且將肝臟組織儲存於冷凍器中直至將其運送至Empirico。在肝臟活檢體收集之後,在第-2天或第28天,所有動物不存在異常臨床觀測。在設定為5000 rpm,持續兩個10秒循環之Percellys 24組織均質器(Bertin Instruments)中,使用軟組織均質化套組CK14 (Bertin Instruments,目錄號P000933-LYSK0-A)在均質化緩衝液(Maxwell RSC simplyRNA組織套組)中處理肝臟樣本。在Maxwell RSC 48平台(Promega Corporation)上,根據製造商之建議純化來自肝臟溶解物之總RNA。使用Quanta qScript cDNA SuperMix (VWR,目錄號95048-500),根據製造商說明書進行cDNA之製備。在PerfeCTa qPCR FastMix反應混合物(VWR)中使用針對長尾獼猴MST1 (ThermoFisher,分析號Mf01117426_g1)及長尾獼猴管家基因GAPDH (ThermoFisher,分析號Mf04392546_g1)之TaqMan分析,藉由RT-qPCR在雙工(biplexed)反應中評定肝臟MST1 mRNA之相對含量,重複三次。在QuantStudio™ 6 Pro 即時PCR系統上評定樣本。使用△-△Ct法計算MST1 mRNA之相對量。相對於第-8天之群組平均相對MST1 mRNA含量顯示於
表 22中。與藉由AlphaLISA所量測之血清MSP含量降低一致,相較於給藥前第-8天含量,用5 mg/kg測試品ETD01821、ETD01822、ETD01823或ETD01826處理引起在第28天MST1 mRNA之肝臟含量降低。 表8.實例siRNA序列
以下實例證實,當組合靶向額外目標(MTRES1)之寡核苷酸時,本文所描述之GalNAc部分在活體內之效用。測試設計成與人類、小鼠及石蟹獼猴 MTRES1mRNA具有交叉反應性之若干siRNA在小鼠中之活性。將siRNA與GalNAc配體ETL1或ETL17連接。siRNA序列顯示於 表 23中,其中Nf為2'氟基修飾之核苷,n為2' O-甲基修飾之核苷,「d」為去氧核苷,且「s」為硫代磷酸酯鍵聯。 The following examples demonstrate the utility of the GalNAc portions described herein in vivo when combined with oligonucleotides targeting an additional target (MTRES1). Several siRNAs designed to be cross-reactive with human, mouse and macaque MTRES1 mRNA were tested for activity in mice. Ligate siRNA to the GalNAc ligand ETL1 or ETL17. The siRNA sequences are shown in Table 23 , where Nf is a 2' fluoro-modified nucleoside, n is a 2' O-methyl modified nucleoside, "d" is a deoxynucleoside, and "s" is a phosphorothioate Ester linkage.
對六至八週齡雌性小鼠(品系ICR,n=3)在第0天給與皮下注射單次200 μg劑量之結合GalNAc之siRNA或作為媒劑對照的PBS。Six- to eight-week-old female mice (strain ICR, n=3) were given a single 200 μg dose of GalNAc-conjugated siRNA or PBS as a vehicle control subcutaneously on day 0.
在注射後第10天將小鼠安樂死,且自各小鼠收集肝臟樣本並置於RNAlater (ThermoFisher目錄號AM7020)中直至處理。藉由在均質化緩衝液(Maxwell RSC simplyRNA組織套組)中,使用設定為5000 rpm持續兩個10秒循環之Percellys 24組織均質器(Bertin Instruments)均質化肝臟組織來製備總肝臟RNA。在Maxwell RSC 48平台(Promega Corporation)上,根據製造商之建議純化來自溶解物之總RNA。使用Quanta qScript cDNA SuperMix (VWR,目錄號95048-500),根據製造商說明書進行cDNA之製備。在QuantStudio™ 6 Pro 即時PCR系統上,使用針對小鼠
MTRES1(ThermoFisher,分析號Mm01229834_m1)及小鼠管家基因PPIA (ThermoFisher,分析號Mm02342430_g1)之TaqMan分析,以及PerfeCTa® qPCR FastMix®, Low ROX™ (VWR,目錄號101419-222),藉由RT-qPCR評定肝臟
MTRES1mRNA之相對含量,重複三次。將資料標準化為接受PBS之動物中之平均
MTRES1mRNA含量。結果顯示於
表 24中。相對於接受PBS之小鼠,注射ETD01597、ETD01955及ETD01958之小鼠之平均肝臟
MTRES1mRNA在第10天具有實質上更低含量。 表23.實例siRNA序列
雖然本文已顯示及描述本發明之較佳實施例,但熟習此項技術者將明白,此類實施例僅藉助於實例提供。熟習此項技術者可在不脫離本發明之情況下想到許多變化形式、改變及取代。應理解,本文所描述之本發明之實施例的各種替代方案可用於實踐本發明。預期以下申請專利範圍界定本發明之範疇,且藉此涵蓋在此等申請專利範圍及其等效物之範疇內之方法及結構。While preferred embodiments of the invention have been shown and described herein, it will be understood by those skilled in the art that such embodiments are provided by way of example only. Many variations, changes and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It is intended that the following patent claims define the scope of the invention and that methods and structures within the scope of such claims and their equivalents are thereby covered.
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